House, a risky, challenging and altogether different kind of medical drama, premiered on November 16, 2004, and turned the genre on its head with a true antihero lead: a doctor who has overt disdain for his patients — and people in general. But thanks to compelling writing and a career-defining performance by British improv-comedy vet Hugh Laurie, the show stayed on the air for eight seasons of abuse (both drug and verbal) and countless diagnoses that were almost never lupus. As House prepares to sign off for good (Monday, May 21 at 8/7c on Fox), TVGuide.com talked to the show's creators and cast about building the Emmy-winning drama from the ground up. This is the first of a two-part series.

Executive producer Katie Jacobs and her partner Paul Attanasio were coming off the failed medical drama Gideon's Crossing when a new idea struck: make a medical show in the vein of another genre-upending show: CSI.

Katie Jacobs: There was a column in the Sunday New York Times magazine called Diagnosis, written by Lisa Sanders. Basically, it lists a series of incongruous symptoms... and then it took 1,200 words to discover the mystery of what the diagnosis was. It was as simple as that — the notion of a medical mystery with the symptoms as the suspects.

David Shore (creator, executive producer): The networks got all excited about the [medical mystery idea] and there was a little bit of a bidding war. It scared the hell out of me because I'm going, "I'm not sure we have a series yet." Germs don't have motives. People watch mysteries not because of whodunit, but because of "why done it." That's what the show became about: Why do people do the things they do? I spent months and months trying to figure out what that first story would be and who the people would be. I needed this character at the center who's fascinated by the things people do and is looking for logical reasons for everything.

Katie Jacobs: The idea for the character came from [thinking], "What do doctors really say when you leave the room? How do they really talk to each other?" "Everybody lies" comes from the notion of [someone] giving their medical history to the doctor. He says, "How many glasses of wine do you have during the week?" You say two, and he writes four. The other thing that really mattered is that when you go into a hospital, more often than not, they do not know what's wrong with you. They figure out what's wrong by trial and error. It's an uncomfortable place to live, but it's true, and I think people really responded to it.

David Shore: Sherlock Holmes was a bit of an inspiration. [I wanted] to make the show about somebody who cares more about the puzzle than about the lives, which then led to thinking about what's more important: motives or results? And what matters more: the emotion or the intellect? House is a bit of my alter ego on a certain level. Most of his attitudes toward things are mine. He's a lot smarter than I am and a lot right-er than I am. So he can get away with saying these things. But the things he says tend to be things that I've thought.

Casting the title character, Dr. Gregory House, a pill-popping diagnostician with a pronounced limp, was crucial. Although the producers saw a number of actors, they were instantly drawn to Hugh Laurie, one half of the British comedy duo Fry and Laurie. At the time, his most recent work stateside was as the wholesome, friendly dad in the film Stuart Little. He impressed everyone.

Bryan Singer (director, executive producer): I was very adamant about the show being called House. There was some concern on the part of the network that the show would then become reliant on the actor playing House. And I said to them, "Have you read the script? He's the guy. The show will always be reliant on his character."

Katie Jacobs: We knew that House was handicapped. The idea was that he doesn't want to see patients, but he really doesn't want to be seen by patients. At first, I remember he was in a wheelchair... and for a short while, I imagined that he had a scar like Beauty and the Beast or Phantom of the Opera. It would have been awful. But the cane was the right choice. Once it was a cane, it needed to be someone who could hold the center walking down that hallway. Hugh was the only one.

Bryan Singer: I had seen a lot of foreign actors and I was very concerned that they would have trouble with the dialect, particularly with all the medical terminology. And there wasn't anyone with a strong voice and a magnetic presence. A tape came up, which was this very rough, self-made audition tape that was done in a restroom in Africa by Hugh Laurie, who I had never heard of. He happened to have a lot of razor stubble and the quality of sound was like one of those Bin Laden videos. It was really bad. And yet, something about his voice really appealed to me. There was a smoothness to it and an articulation that I found really could carry this character. I turned to Paul and Katie and I said, "This is what I'm talking about! This is what we need — an American!" And they looked at me and said, "He's British."

Katie Jacobs: When I put in the tape of Hugh's audition, I saw Bryan Singer get up from behind his desk and walk closer to the TV. And if you're worth your salt as a producer, you don't forget that.

David Shore: Hugh does things I just can't imagine another human being doing. He tells a joke in the darkest scenes and you don't lose any of the depth. He frees me up as a writer to write anything for that character. As long as there is truth behind it, it will work because of him.

Katie Jacobs: What separates Hugh is his ability to tell a joke, yes. That gets you far in terms of forgiveness, but not far enough. What Hugh also has to offer innately, just as an actor, is when the camera is up close, you can see behind his eyes. He can say one thing and still let you know he's deeply wounded.

David Shore: There was hesitation [by the network] about House being addicted to Vicodin, but that hesitation was a good hesitation. It was one of the very few notes they had for us. The note was, "Do it if you want, but if you do it, do it honestly and don't do it as a joke." We never intended to do that. We intended to go with this as a real issue, a real problem, a real dilemma for this character.

Katie Jacobs: You call him a drug addict, and that's true, but he's popping all that Vicodin because he's in pain. You know he's arrogant and he's the smartest kid in class. He's like a huge adolescent. But the abuse of Vicodin also allows you to know he's vulnerable and breakable.

With Laurie cast in the lead role, the producers set about finding his best friend, James Wilson, his boss, Lisa Cuddy, and the three fellows who would make up House's diagnostic team.

Bryan Singer: Many years ago, I made a short film with an old neighbor of mine, Ethan Hawke. Ethan introduced me to Robert Sean Leonard, and I showed him a rough cut of my little student film. Bobby gave me a check for $1,000 and wrote a letter saying, "Keep doing what you're doing." I never forgot that. When he came up on my casting list, I said, "Bobby can do anything. He has the role." I wouldn't have cast him if I didn't know he was brilliant, but literally the moment he came across my desk, I said, "He's going to be Wilson and that's just that."

Jennifer Morrison (Dr. Allison Cameron): The day of my meeting, it was raining in L.A. It was a mess outside, and I didn't have an umbrella. I kept thinking I just needed to get in there and clean myself up and go in and do it. I walked in, and Bryan Singer was sitting in the lobby. There was no chance to ever put myself together, so I walked in like a drowned rat.

Bryan Singer: Since I basically gave the network only one choice for the Wilson role, the network said, "Bryan, we'd really like to get a few choices just so we can be part of the process. So for [Cameron] I sent them reference tapes from three girls. One I don't remember and there were two others. One was a blond girl and the other was a brunette. And both were Jennifer Morrison. This just makes me seem like an idiot, but I didn't know that. They said to me, "Bryan, we didn't appreciate your joke." I said, "What do you mean?" They said, "You sent us two of Jennifer Morrison." And I said, "Well, she must be perfect for it."

Jennifer Morrison: I didn't hear back quickly, so I was like, "Oh shoot, I guess it didn't go well." And I was kind of bummed about it. I had these other test offers, but I felt like this was the one that would have been really special. But I guess it turns out my only competition was myself with blonde hair.

Bryan Singer: I found [Cameron] to be in Jennifer's personality. She's someone who is beautiful but doesn't want that to be their identity. ... I saw her as a character who had some holes. There was loss in her life and no matter how much abuse House could dish out, in some strange, parental way, he was filling the void that the character had at that time in her life.

Jennifer Morrison: She's someone who's drawn to talent and to passion, so House's rough exterior was never really a problem for her. She was seeing that he was saving lives, that he was passionate about saving lives, that he was an incredible talent, and those were the things that were attractive to her. Those were the things that turned her on in life.

Bryan Singer: I thought Jesse Spencer was a nice pairing with Jennifer, both physically and his energy. Jesse had a certain kind of confidence. He carried his looks more comfortably than Jennifer. I always looked at the two young doctors as a team. It was a lot like casting Usual Suspects for me. When I cast Benicio Del Toro and Stephen Baldwin, they were like a team in my mind. It was the same thing here. These were the two young doctors, and they had to kind of jive with each other.

Omar Epps (Dr. Eric Foreman): Foreman really has conviction in what he believes. Foreman and House are alike in some ways, but House is probably a bit more jaded. In Foreman seeing their similarities, he realized what he doesn't want to be like.

Bryan Singer: Omar's got great eyes, and I knew he'd be rolling those eyes in every episode for the first season. Omar Epps is the kind of cool that House can't be. Foreman, to me, was formidable. Everyone else [House] can abuse. Foreman is your formidable opponent.

David Shore: Right from Day 1, there was that sexual tension between [House and Cuddy]. It was just the way those two actors played it. Even if I had tried to not do it, it was going to be there and I enjoyed it.

Bryan Singer: I cast Lisa Edelstein because I saw her play the hooker in the pilot of The West Wing and I thought she was fantastic. I saw her as the hottest hooker in Washington, D.C., but [then-Fox Entertainment President] Gail Berman knew her from Ally McBeal, where she played a transgendered woman. She was like, "I think she looks like a man," and I said, "No. She's hot." Clearly it was a matter of perception. But when I screened the pilot at my friend's bachelor party before it was aired, all my buddies in Jersey were like, "Yeah, she's hot." I made the right choice. (Edelstein declined to speak with TVGuide.com for this story.)

The pilot episode was shot in Vancouver, and Fox put the show on its schedule in the fall of 2004, opting to premiere it in November after the World Series ended.

Hugh Laurie (Dr. Gregory House): I thought the pilot was good. I thought this was a good and interesting story with good and interesting characters. That didn't mean that anyone was going to watch it. That was a big surprise.

Robert Season Leonard (Dr. James Wilson): I remember watching the pilot and showing it to my wife and thinking, "Wow, this is really good. I would watch this. So it's never going to run, because everything I like gets canceled." I liked My So-Called Life. So I was surprised when it ran. It was a tight race for a long time. We didn't have great numbers, but the show has always been good. And then they put us after American Idol.

David Shore: It brought an audience to the show that stuck around, and I am obviously grateful for that. It gave people a chance to sample the show. They sampled it, and they liked it, and that was wonderful.

Katie Jacobs: If you have an audience, and you're growing, you no longer have to think about fighting for your show. Then it's a privilege to sort of use your imagination as to where it could go.

In Part 2: Breaking the formula and blowing up the team, the era of House and Cuddy, and the strength of the House-Wilson bromance, all the way to the end.

IN his last week as the irreverent, idiosyncratic, inimitable television doctor Gregory House, Hugh Laurie acknowledged that he had yet to process fully that he would soon be shedding a character who had inspired him, obsessed him and unnerved him for 177 hours of drama.

On Monday Fox will broadcast the final episode of the eight-year run of “House,” an end that was not forced by ratings (which have only recently dropped from hit levels to more modest territory) but comes willingly after the show’s originator, David Shore, figured out how to wrap up the series.

Though Mr. Laurie has acknowledged that there were seasons in the middle of the run that some critics considered formulaic, that was all behind him as he sat in a director’s chair bearing his name on the sprawling, startlingly hospital-like “House” set. “I don’t know if I’m going to break down in a quivering heap or whether I’m just going to drive off the lot without a look back.” He had scenes left, so he still spoke in the American accent that has fooled millions of viewers who never knew he was British.

One thing he said was certain: “I will miss him a lot.”

He won’t be the only one. Beyond the viewers who came to embrace the weekly dissections of arcane cases, diagnoses led by the most brilliant riddle-solver since Sherlock Holmes (who inspired the character in the first place), “House” proved to have astonishingly wide appeal.

It says so in Guinness World Records, 2012 edition, which lists “House” as the world’s most popular television show, with 81.8 million viewers in 66 countries.

“That is absolutely amazing to me,” Mr. Laurie said, “only because I think the character and the stories have been so intensely verbal. I don’t mean just technical, but it’s very idiomatic, it’s very metaphorical. Some of the ideas that have been played with, how they translate into Turkish, I don’t really know.”

But they do, and many other languages as well. Omar Epps, who played the tightly wound but vulnerable Dr. Foreman, often at odds with House’s rule-shattering methods, said he had the experience of being on a “remote little island off Italy with people calling out to me, ‘Hey, Dr. Foreman.’ ” He added, “Something like that just wows you.”

Mr. Shore, who created Mr. Laurie’s character and remained on the show for its full run, also directed the series finale. Some of the secret elements have leaked, including a roster of familiar guest stars, as well as the episode’s title, “Everybody Dies,” which echoes the axiom that House has lived by: “everybody lies.”

Mr. Shore acknowledged the emotion of letting go, saying the sense of achievement he felt as his creation wrapped up was accompanied by two elements of disbelief: that the show lasted this long and that it was really coming to an end.

“It’s very surreal,” Mr. Shore said, taking a break from an intense scene that required no fewer than 16 takes, rarer in TV than in movies, one sign of the care that the show has always taken. “Part of me is going: we’ve just started. Aren’t we on Episode 6?”

But, he said, another part is amazed that a show built around a damaged, supremely cynical character who violated virtually every network rule about centering shows on likable people, lasted so long and did so well. “I never dreamt it would have this kind of success,” Mr. Shore said.

What distinguished “House,” beyond its production values, writing and acting talent, headed by the career-defining performance of Mr. Laurie, was the arresting figure at its core (one who was arrested at the end of last season.) House, the character, emerged at a time when television drama was just beginning to embrace the idea that a protagonist could be judged by the content of his flaws, as much as or more than his strengths.

About five years before House arrived, Tony Soprano made the world of cable television a safe haven for a new sort of antihero (that is, a frighteningly amoral one). He begot the broken lead characters in shows like “Breaking Bad,” “Mad Men,” “Homeland” and “Nurse Jackie.” But those are all cable series. “House” took a plunge into the broader pool of network drama, which had traditionally demanded champions not chameleons.

The character of House was defined by such outrages as authorizing break-ins of patients’ homes and manipulating the love lives of his staff. There were sexual comments that would inspire lawsuits in most workplaces and a drug addiction that led him to extreme and often extralegal steps to acquire copious quantities of Vicodin.

As Alessandra Stanley wrote in The New York Times, “House stands out by defying the conventions of network television: he is a wisecracking recluse who resists every attempt to be turned lovable or even likable. He feels malice toward all.”

Mr. Shore said he hoped he had had a small part in making networks realize that “this kind of character can be appealing.”

House was also a relentless prankster, most often targeting the only real friend he had, his Watson, Dr. James Wilson, played by Robert Sean Leonard. (This season House hired a child actor to fool Wilson into thinking that he had fathered a son.) Mr. Leonard admitted to being the cast member happiest to see the series end — “I hate film acting; I’m the laziest man alive” — but said House’s shocking comments had always been mitigated by the fact that “it’s not unpleasant to watch him saying them.”

Mr. Leonard added: “People say, why is my character friends with him? And I say, why do you watch him? He’s antisocial; he’s brilliant; he’s frustrating; he’s irreverent; he plays jazz piano; he drinks bourbon; he’s very wise. What’s not to like?”

Mr. Shore, naturally, said he agreed, but noted that House was “heroic in a very untraditional way,” adding: “He didn’t care about anything but the truth.” As Mr. Shore saw it, “House” wasn’t even a medical show: “That’s not the driving force of it: it’s truth-telling.”

Being truthful, Mr. Shore conceded that the final season had not been the easiest. Contract issues cost him one of the show’s crucial characters, Dr. Lisa Cuddy (Lisa Edelstein), whose tortured romance with House drove the plot. Ms. Edelstein’s departure forced a story line that many fans questioned, with House in prison, after driving his car into Cuddy’s living room.

“We got such blowback,” Mr. Shore said. He defended the move as a kind of punishment that House exacted on himself. A rational character, “he had to be driven to that by some very, very strong emotional forces,” Mr. Shore said, adding:

“That’s probably the biggest message in the series: think about things a little longer because our knee-jerk reactions are going to fool us every time.”

After Mr. Laurie had wrapped for the day, saying goodbye to two regulars he would have no more scenes with, he dropped back into his chair, unaccountably fresh despite the workload of being in virtually every scene. (Mr. Leonard: “I don’t know how he does it. He’s completely insane. If I was Hugh Laurie, I would have had a gun in my mouth years ago.”) Reality set in more pressingly. “As we approach the last days, I’m assuming crash position getting ready for re-entry,” Mr. Laurie said, sounding plumily British again.

He said he had always found it easy enough to shift out of the vocal part of House — the character, not so much. For much of the series, he said: “I put him on like a suit of clothes, and I didn’t take it off. I didn’t send it to the dry cleaner as often as I should have. I kept him on.”

He added: “It sounds pretentious when actors talk about the cost of something because we’re hideously spoiled and overcompensated. But having to inhabit a character who is that cynical and morbid and occasionally suicidal, a character that tormented, can get to you after awhile. It can start playing tricks on you. You start wondering why you’re doing it, whether there’s any value to it.”

He paused to consider how that sounded and said: “A sane person would say that’s ridiculous, it’s only a television show. But if we believed it was only a television show, it wouldn’t be a television show — it would be a canceled television show.”

Like Mr. Shore, Mr. Laurie spoke with the sensitivity of the complicated man he had created.

“I like him very much,” Mr. Laurie said. “I think he’s lonely. He has a wonderful sense of humor. He’s got a wonderful sense of playfulness about him. He’s just calibrated differently. He’s on the side of the angels, but that doesn’t mean he has to be an angel. He most definitely isn’t. But I think somewhere within him there burns a very fierce and righteous flame.”

The description was entirely in the present tense. When that was pointed out, Mr. Laurie said: “That’s very odd. I was not aware I was doing that. I have not come to terms with it.”

The ending, that is. Mr. Shore said that early in the final season he put together a plan for ending the series. How House goes out will be unraveled following an hourlong retrospective that Mr. Laurie put together. Mr. Shore offered one hint about House’s fate when asked if he would consider — as has often been suggested of well-loved shows as they exit — a “House” movie down the road.

“I wouldn’t say no,” he said. “If I had the right idea and everybody was on board.” He acknowledged that these things almost never happen: “It’s very tempting to just say maybe, because it makes you feel maybe it’s really not the end.”

But of course, for the series, it is.

“I am immensely proud of the fact that it is really a show about something,” Mr. Laurie said. “It isn’t about car chases, or vampires, or whether two models will go to bed together. It is about the play of ideas and emotions and philosophies, and ethics and manners. It is actually about something.”

That is something, he added, that he is unlikely to encounter again. “I am an incredibly lucky person to have found one experience like this in my life,” Mr. Laurie said. “Most actors could live many lives without coming across something as joyous as this.”

TV has had its fair share of will-they-or-won't-they romantic relationships. Heck, whole shows have been built around this premise.

But there's something to be said about those tried and true couplings — the ones where no matter what, you know the two people involved will always be together.

This is the case on Fox's beloved medical drama "House."

For eight seasons, Dr. Gregory House (Emmy-nominated actor Hugh Laurie) has saved lives, broken the rules and even a couple of hearts but he has never given up on his bond with his best friend Dr. James Wilson (Robert Sean Leonard). In turn, it has been Wilson who has always been there for House even when he didn't deserve the support.

Arguably one of the best relationships on TV, House and Wilson's bromance is one of the things fans will miss when "House" comes to an end Monday night. Upping the ante is the heartbreaking possibility that Wilson will die of cancer before House gets out of prison because he played a stupid prank and violated his parole.

Will House get to say goodbye to his best friend? How will the show end?

Fans are on pins and needles to find out. And that's just what the show's creator and executive producer, David Shore, wants. More than anything, it has been a show about House and Wilson and it will end with a focus on them, he says.

"There are a lot of explorations on TV of romantic relationships, and some are good and some are bad," Shore says. "I think there are very few explorations of male friendship. Not just a wingman type friendship. We really explored two friends and their relationship. It's something we've done well that isn't done that often. I'm proud of it.

"So it felt like it's the right idea to explore it as we headed toward the end of the series."

Paul Levinson is a professor of communications and media studies at New York's Fordham University. He says the word "bromance" doesn't even begin to describe the 20-year friendship between House and Wilson. Their bond is the heart of the show, Levinson adds.

"It's much more profound than a bromance," says Levinson, who is a huge "House" fan. "It's one of the best relationships we've seen on television. House is a genius who is able to function because he has Wilson as his friend."

To best understand their friendship, it helps to look at House as a modern-day Sherlock Holmes diagnosing illnesses no one else can with Wilson playing the role of Doctor Watson, the ever dutiful sounding board and moral compass.

"David Shore constructed these characters through his love for the Sherlock Holmes mysteries," says Dale E. Turner, an actor and Ann Arbor native who guest-starred on "House" during the drama's sixth season. "House is always looking to solve the next great medical puzzle and Wilson, his faithful but put-upon partner, is there to provide the pragmatic point of view in all situations.

"Both of these brilliant doctors have love, respect and admiration for each other and seem to go out of their way to not let each other know it."

It's true, the two men have never said "I love you," but the love is real. When trying to convince Wilson to consider chemotherapy in a recent episode, House said: "I need you. I want you to be around for as long as possible because I don't know what I would do without you."

If that's not a profession of love, what is?

While the road to best-friends-forever land hasn't been smooth — Wilson dumped House and blamed him for indirectly causing Wilson's girlfriend Amber's (Anne Dudek) death in season four — the two have kept their friendship alive and if fans are lucky, the finale will show them together still.

"That Wilson was able to forgive House shows just how strong their friendship is," Fordham's Levinson says. "That's good writing."