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.

Charlotte, an older woman who has spent the last six months taking care of her dying husband Eddie, is rushed to Princeton Plainsboro after collapsing from respiratory failure. The couple becomes a double mystery for the team when Eddie begins to improve as Charlotte’s condition worsens. The previously unthinkable becomes real when it seems that Charlotte will die before Eddie, and the team will be forced to make a difficult decision.

A wealthy businessman brings his teenage son, who is suffering from inexplicable stomach pains, to Princeton Plainsboro and insists on having Dr. House handle the case. The father of the patient believes the karmic penalty of his financial success is that he is victim to personal tragedy, and that the answer to his son's medical mystery lies in a reverse of fate rather than medical treatment. Meanwhile, Foreman and Chase prepare to present information on the Dibala case.

During a day in the life of Princeton Plainsboro's Dean of Medicine, Dr. Lisa Cuddy, the inner workings of the hospital are seen through her eyes. This day proves to be especially trying as Cuddy wrestles with myriad hospital issues and staff disputes that test her perseverance and skills as an administrator, all while juggling issues in her personal life.

House and the team take on the case of a woman Julia, who is in an open marriage and becomes ill during a date with her on-the-side boyfriend. As perplexing as the case is, Julia's happy and healthy, yet polygamous relationship is equally baffling to the team. Meanwhile, House tests Wilson's relationship with Sam.

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.

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.

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 prosecutor suffers from what he believes to be cardiac arrest during an interrogation at the witness stand. The team's preliminary diagnosis is hyper-anxiety, but when Adams and Park investigate the patient's home and find a hidden arsenal of firearms, they uncover a more alarming and deep-seated psychological disorder.

House and his team are placed under review after a staff member gets hurt.

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.