Dr. Gregory House, a drug-addicted, unconventional, misanthropic medical genius, leads a team of diagnosticians at the fictional Princeton–Plainsboro Teaching Hospital in New Jersey.
After recovering from his gunshot wounds, House works feverishly on two cases at the same time: a paralyzed man who drove his wheelchair into a swimming pool and a woman who became paralyzed after a yoga session.
House and the team treat a young boy who claims there is a tracking device in his neck and believes he has been the subject of alien experimentation. Cameron is outraged when she learns Cuddy and Wilson have been lying to House about the diagnosis on his last case.
House puts a well-known medical researcher through a battery of tests to determine why he collapsed in his lab. When the team is unable to diagnose the problem, the doctor asks the team to help him end his life. House is forced to use his cane again after the ketamine has worn off as he deals with a clinic patient's teenaged daughter who has a crush on him.
When doctors are unable to diagnose why a severely autistic boy screams loudly for no apparent reason, House takes the case. As the boy's condition worsens, it becomes obvious that House relates to the boy because he has no social niceties.
House takes the case of a young woman who has been rushed to the hospital with problems breathing and severe stomach pain after she and her husband were robbed. After her husband collapses, the team believes the couple's illnesses are related. Meanwhile, Michael Tritter, a clinic patient, causes problems for House that could have serious ramifications.
The team encounters logistical problems while trying to run tests on a 600-pound man due to his extremely large size. Meanwhile, House spends the night in jail after being arrested by Detective Tritter for various charges, including resisting arrest.
House decides to awaken a comatose patient so he can question the man regarding the family history of his son, who may have a genetic condition and the father is the only living relative. Meanwhile, Wilson confronts House about the stolen prescription pad as Tritter approaches Cameron, Chase, and Foreman in an attempt to divide the team and reveal their loyalties.
An 18-year-old teenager is brought to the hospital after having a heart attack. House reviews the boy's file and believes he has the diagnosis. He then turns the case into a game by sealing his opinion in an envelope and challenging Cameron, Foreman, and Chase to guess House's diagnosis on their own. Meanwhile, Tritter's actions against Wilson continue to strain the oncologist's relationship with House and destroy his ability to practice medicine.
House takes the case of a young girl who has been diagnosed with pancreatitis. When he takes her divorced parents to court to force them to allow treatment because they can't agree, the judge awards guardianship of the girl to Cuddy. Meanwhile, Tritter continues his strategy to force House to admit to his drug use by offering one of the team members a deal.
Wilson arranges for House to make a deal with Tritter, but House refuses. Meanwhile, Cuddy cuts House off Vicodin and removes him from the team's case: a 15-year-old little person who entered the hospital with a collapsed lung and anemia.
House splits his time between treating a firefighter for uncontrollable shivering, giving Tritter a piece of his mind, and handling his trial for forging prescriptions.
While House is forced to work full-time in the clinic and deal with a rape victim who insists on confiding with him, Cameron deals with a terminal cancer patient trying to take advantage of her state of mind.
House and his staff must deal with a teenage Gypsy boy suffering from inexplicable respiratory distress. However, House has bigger issues on his mind: Cuddy has given away his handicapped spot.
It's Valentine's Day, and Cuddy has a blind date. Meanwhile, House leaves ER duty to take the case of a child patient named Hannah.
House encounters a brain-damaged musical prodigy with inexplicable abilities while the team faces serious concerns about House's own health.
The ex-marine that saved House's life, in a dream he had the day before, is admitted in the hospital with symptoms resembling Gulf War Syndrome. While House is busy dealing with his own health issues, and Chase and Cameron are too busy with each other, the ex-marine gets worse.
A famous celebrity photographer suffers from a stroke while being pregnant at her early forties. House and his team have to deal with a great dilemma, save the mother or her unborn child.
On House and Cuddy's flight from Singapore a passenger gets ill and Cuddy suspects an epidemic. At the hospital, Wilson leads the team as they deal with a middle-aged woman suffering from seizures.
A 6-year-old girl suffers ailments expected in patients much older. Tensions between Chase and Cameron lead House to intentionally assign them to the same tasks, including investigating the young girl's home.
The doctors try to find what's wrong with a scam artist who collapses after her brain "freezes," but the case becomes personal for Foreman.
Wilson prepares to transplant bone marrow from Matty to his brother Nick. But when Matty gets sick, the team must cure him as he's the only safe donor. Meanwhile Foreman deals with the consequences of his mistake and House has a battle of wills with his new pet Hector.
The team deals with a 19-year-old college student, while Foreman suddenly and without a reason hands in his resignation. House seems to have already found Foreman's replacement, an attractive nutritionist named Honey.
House treats a 16-year-old chess prodigy who gets everyone on the team annoyed with his behavior. Foreman is upset with House because he thinks his boss sabotaged his job interview with another hospital.
A Cuban couple attempt to get to America by raft... to see House about the wife's heart condition. But when she gets worse House wonders if someone on his staff messed up. Meanwhile Foreman prepares to leave and his departure threatens to shake up the entire team.