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.
House is serving out a lengthy prison sentence for his various misdeeds, including his trip outside the country in an attempt to escape responsibility. Entirely cut off from his old life, House determines his current problems are the result of his inability to deal with people. Feeling he will never be able to practice medicine again, he plans instead to go back to university to earn a doctorate in physics - a field that will all but assure his isolation from other human beings.
After losing a bet with Wilson over a boxing match, House is convinced that his fighter has an underlying medical condition that cost him the fight. While he tries to prove it, he leaves his team alone to help a bomb scientist who suffered a seizure. Meanwhile, House may be experimenting with a new drug to help his leg pain.
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.
Masters faces a career crossroads on her last day as a medical student and struggles with the choice to continue on the path to become a surgeon or to accept the rare opportunity to join House’s team officially. Meanwhile, the team treats a 16-year-old girl who inexplicably collapsed days before embarking on an ambitious sailing tour around the globe. Despite the patient's life-changing diagnosis, the patient's family insists on getting her back on the seas in time for her potentially record-breaking launch. But to the team's surprise, including House, Masters makes a bold decision regarding the patient’s treatment.
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.
The team treats a professional bull rider who is attacked by a bull. The team must determine the causes behind the patients disappearing symptoms and seizures while taking House's advice from outside the hospital as he attends to issues unrelated to the case. Meanwhile, Masters develops a crush on the patient.
Tension reaches new heights when Cuddy faces sobering news that propels her to reevaluate her priorities. While House is distracted by his concern for Cuddy’s well-being, the team treats a teenage patient whose worsening symptoms and suspicious body scars indicate more than just physical illness. Sensing the teen’s troubled emotional and mental state, Taub turns to the patient’s personal life for clues and uncovers disturbing home videos that could put the lives of his peers in danger. Meanwhile, Cuddy remains hopeful that House will be fully present when she needs him most, and a series of dreams, including a musical scene choreographed by Mia Michaels, provide glimpses into her life and her relationship with House.