A professional bicyclist is brought in after collapsing during a race, but House doesn't want to treat him because he thinks the athlete is taking performance-enhancing drugs. House only becomes interested when the patient admits to taking the drugs.
A death row inmate is felled by an unknown disease and House decides to take on the case, over Cuddy and Foreman's objections. House also has to deal with Stacy who is working closely with him, while Cameron has to cope with a dying patient.
When Stacy insists her husband Mark get tests, House insists he can handle things. But despite the fact Mark's tests prove negative, his steadily growing symptoms indicate he is dying. While House struggles with the mystery and make increasing demands on his staff, Wilson worries about House's emotional well-being, and Cuddy considers adding a new employee to the clinic.
House apparently triggers a stroke in a clinic patient, but the major topic of discussion is House's imminent date with Cameron, The team must deal with the patient's odd lifestyle, overbearing "friend," and reluctant parents in order to stop the strokes and try to save his life. Meanwhile, Wilson, Cuddy and the team offer House and Cameron advice while laying odds on the outcome.
House's ex-girlfriend Stacy Warner returns – not for House but to get help for her ailing husband. While House decides whether or not to take her case, Cuddy forces him to present a lecture to a class of medical students. As he weaves the stories of three patients who all present with a similar symptom, House gives a lecture the students will never forget.
During an meningitis outbreak which overwhelms the clinic, House is drawn to a single patient: a 12-year-old whose symptoms don't quite match everyone else's. House, Foreman, and Chase must devise ingenious ways and locations to treat the girl's delicate condition in the middle of the chaos, and make an unexpected discovery. Meanwhile, House asks Cameron to come back to her job but she has one requirement that he might not be able to meet.
At a high-level campaign fundraiser, a senator becomes violently ill. Vogler forces House to take the senator's case and offers to let off the hook on firing a team member if he'll deliver a speech on behalf of Vogler's pharmaceutical company. It looks like the senator has AIDS but House refuses to settle for the easy answer. And House ends up giving the speech, but it doesn't go quite as Vogler planned.
While House and his team scramble to discover what's causing brain and kidney dysfunction in a pregnant woman, Vogler is working to get House fired after House's pharmaeutical speech. House determines the illness, but the woman and her husband must struggle with an emotional and heartbreaking choice: choose between her or that of her unborn child. Vogler calls for a vote to remove House, but when Wilson refuses to make the vote unanimous, Vogler threatens to take his money if Wilson isn't voted out. Finally, Cuddy must take a stand against Vogler.
House must fire one of his doctors and leaves them to think about it while they deal with an overweight 10-year old child who suffered a heart attack as the result of taking diet pills. House is also faced with a woman who won't accept surgery for a 30 lb. tumor because she wants to remain overweight.
