Thirteen has been in prison for the past year, but the real mystery for House is what she did to get there. At the hospital, the team treats a science teacher suffering from severe respiratory illness. Taub tries to get back into the dating scene, but winds up retreating to his old habits.

When House discovers that the experimental drug he's been using causes fatal tumors, he decides to attempt to excise them himself. However, he can't complete the surgery and ends up needing Cuddy's help. Meanwhile, Thirteen's friend from prison (Amy Landecker), a relapsed drug user, arrives at her apartment needing medical care after being stabbed. With her friend unwilling to go to the hospital, Thirteen enlists Chase's assistance when the friend loses sensation and movement in her arm. Also, Taub receives some unexpected news that could change his life.

The team treats a performance artist (Shohreh Aghdashloo) who deliberately made herself ill with the aim of turning the diagnostics department into her new masterpiece, as House must decide which of her symptoms are real, and which are self-inflicted. As the case progresses, House vows to make changes in his life, but remains rooted in old habits. After the case is over, House finally deals with his anger over the breakup and lashes out by driving through Cuddy's dining room and escaping to a beach.

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.

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.