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.
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 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.
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 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.
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.
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.
As House and his team are working on the diagnosis of a man with a giant, swollen tongue, the husband of a former patient walks into House's office and shoots him. House continues to treat his patient from his ICU hospital bed with the shooter, who has been shot by hospital security and hand-cuffed to his bed, as his roommate. When the after-effects of the shooting begin to impact House, he starts to question his own ability to diagnose properly. As his patient's body deteriorates, House struggles through his self-doubt and must trust his team to find a way to solve the case.