Under Cuddy’s pressure to choose his team, House gives the candidates a case of a former punk rock star who is a drug user. Whoever diagnoses the patient is going to have a future as a member of House’s team.

In the aftermath of personal tragedy, Wilson resigns from the hospital... and from his friendship with House. Meanwhile, Thirteen struggles with her personal medical problems while helping treat an executive assistant with a similar situation to her own.

A gun-wielding man from the waiting room at the Princeton-Plainsboro clinic takes House, Thirteen and several patients from the waiting room hostage in Cuddy's office. The man claims to be sick with a long undiagnosed illness and demands medical attention from the best doctor in the hospital, threatening to kill any hostages necessary along the way.

House and the team try to diagnose a man living with severe, chronic pain; Thirteen and Foreman explore their complicated relationship; Cuddy discovers that caring for her baby leaves her with little time to run the hospital.

Cameron postpones her vacation with Chase in order to ask House to accept the case of an environmental radical who collapsed at a protest with unexplainable symptoms. Although suspicious of her motives, House agrees. Since she pushed him to take the case so emphatically, House forces Cameron to take the lead and run many of the tests on the patient. Meanwhile, House is unsure of Wilson’s new healthy diet.

After House’s medical license is reinstated, he reclaims his role as Head of Diagnostics in time to treat Hank Hardwick, an adult film star admitted to Princeton Plainsborough for pulsating eye pain. Meanwhile, Cuddy is reminded that Princeton Plainsborough is not conducive to healthy personal relationships.

This episode has five storylines: When the hospital is sent into lock-down mode due to a missing infant, all of the doctors must remain where they are, leaving Foreman and Taub in the file room, Wilson and Thirteen in the cafeteria playing truth or dare, House in a room with a patient, and Chase with his soon-to-be ex-wife, Cameron, as Cuddy tries to help police locate the infant. This episode is one of the show's rare instances when no medical mystery is presented, though House still deals with his "patient of the week".

A seemingly healthy 14-year-old girl collapses during a skateboarding exhibition; House and Cuddy face the challenge of handling their romantic relationship at work.

The team takes on the case of a lottery winner (Donal Logue) suffering from paralysis and multiple types of cancer, and they must figure out if it his new millionaire lifestyle that is making him sick. Meanwhile, Cuddy's mother threatens to sue the hospital over her treatment, and Foreman and Chase make a bet over who is repressing the uglier side of their personality more.

A teenage boy attempting to follow in his late father’s footsteps as an entertainer is admitted to Princeton Plainsboro with partial paralysis. As the team searches for a bone marrow match, they uncover a disturbing family secret. Meanwhile, House looks for creative ways to remove his ankle monitor so that he can attend a boxing match in Atlantic City, and he treats a patient who is convinced he is suffering from diabetes. Also, Taub faces a tough decision when his ex-wife Rachel tells him that she wants to move across the country with their infant daughter.

Chase's religious faith bubbles to the surface when he treats a young nun. In addition, he and House reach a fundamental disagreement about the patient that may finally end Chase's reputation as House's "yes man" but also bring's House's methods, reputation and objectivity are given more serious scrutiny.

Facing a 6-month jail term, and the realization that he won't be there for Wilson at the end, House finds himself examining his entire life while contemplating a dismal future without his best friend.