House is brought in for a consult on a Death Row inmate (LL Cool J) with mysterious symptoms. Cameron feels the hospital's resources are better used to find a different diagnosis for a young cancer patient (Christie Lynn Smith).^[7] House and Stacy try to establish a good work relationship, especially after he lies to her to secure the transfer of the inmate to the hospital. Wilson coaches Cameron as she struggles to inform the patient of the cancer diagnosis.

A nine-year-old cancer patient (Sasha Pieterse)^[9] is brought before House after she experiences hallucinations. House figures out a way to help her, but it will involve serious risk. They discover she has a tumor on her heart, but when it turns out to be benign, the team decides a clot may be navigating her body. House argues about the nature of the child’s bravery and whether it is a symptom of her illness with his team and Wilson.

Cuddy feels responsible when her handyman (Ignacio Serricchio)^[11] falls off her roof then exhibits unusual symptoms. House's team amputates the handyman's hand to prevent the spread of infection, but when the other hand starts showing similar signs, they must seek out the source before it kills the patient. House ultimately realizes that it's psittacosis, a rare disease associated with exposure to birds, to which the team objects because he doesn't work with birds at any of his jobs. Ultimately, the team finds an illegal cockfight where he works on Saturday nights.

A famous doctor, Sebastian Charles (Ron Livingston), falls ill when working in Africa, and is sent to House for treatment. Tensions mount when House refuses to believe he has tuberculosis, but everyone else believes so. Cameron takes a liking to Charles who asks her out. After Cameron administers a tuberculosis test against House’s wishes, Charles refuses additional tests or treatment. House insists tuberculosis cannot explain all of the symptoms and must persuade Charles to be treated.

A student (Vicellous Reon Shannon)^[14] who just graduated from Princeton experiences severe spasms at a graduation party. Meanwhile, House's parents drop by but he is reluctant to see them, igniting curiosity among the hospital staff.

A famous cyclist (Kristoffer Polaha)^[16] is brought to Princeton-Plainsboro after collapsing during a race. He is surprisingly honest about several illegal medications and techniques he applies to himself, but his sickness is not caused by any of these. House attends and is kicked out of a group therapy session after aggravating Mark. Stacy tells House that she has been seeing a therapist herself in light of supporting Mark during his disability. House breaks into her therapist’s office to photocopy notes from Stacy’s sessions.

House is confronted by Kalvin (Matthew John Armstrong),^[18] a gay man who demands treatment when other doctors diagnose him with AIDS, something he admits he does have. House begins making moves on Stacy using notes he stole from her therapist on her relationship with Mark. Stacy is angered after House reveals that he accessed the notes. Cameron is potentially exposed to HIV by contact with Kalvin’s blood and must have preventative treatment. She confiscates drugs from Kalvin’s bag to help diagnose him. Distressed by her potential exposure, Cameron takes some of the drugs after work. When Chase arrives at her home to console her, they end up sleeping together.

A lawsuit is brought against Chase and House for the death of a mother (Allison Smith) ^[20] who comes in with stomach pain, by her brother (Ryan Hurst). A disciplinary committee convenes to determine whether either of them is at fault. Stacy must question both of them to prepare for the hearing. Chase receives news that his father has died of lung cancer. The committee rules that Chase be suspended for one week. It also determines that House’s work be supervised by Foreman for one month as temporary head of the department.

Anica (Cynthia Nixon) is at an OTB parlor where House observes her have a seizure. She is admitted to the hospital but Cameron wants her to be discharged when they discover she has Munchausen syndrome, however, House believes she has an underlying condition. House clashes with Foreman over the diagnosis. Cuddy toys with making Foreman the permanent department head.

While House and Stacy are in Baltimore, a famed journalist (Michael O'Keefe) collapses in his magazine company's office. While he acts nonchalantly after getting up, it becomes clear from his word-salad-inflected speech that he is suffering from aphasia. Cuddy and Foreman rely on House's insight over the phone. House and Stacy's flight is delayed so they spend more time together. They exchange a kiss but House gets distracted with deciphering the journalist's speech remotely.

Cameron worries about the potential results of her HIV test and House basks in the afterglow of his kiss with Stacy, but Wilson tells him to keep a level head about things. House must dig through the life and lies of a busy housewife (Julie Warner)^[24] to find the true reason why she is showing signs of physical and mental degeneration. Stacy and House have sex, after which House gives Stacy an ultimatum: him or Mark. Foreman's responsibility as temporary department head ends and House regains control. Mark finds House and confesses concerns that he is losing Stacy. Cameron's follow-up HIV test returns negative. Stacy chooses House, but House rejects her based on their past history and dysfunction. Stacy then leaves Princeton-Plainsboro and departs with Mark.

Final diagnosis: Ritalin abuse, then hepatocellular adenoma caused by contraception

The team struggles to diagnose a teen (James Immekus)^[26] suffering from spasms when severe burns following an accident make most of their usual diagnostic tests impossible. Meanwhile, House exacts revenge on a doctor who turned him in for cheating in medical school. House tests the doctor's migraine medicine on himself by self-inducing a migraine. Wilson accuses him of doing so only to take his mind off of Stacy. After solving the medical case, House hires a prostitute.

House treats a teenage supermodel (Cameron Richardson)^[28] who suddenly passes out during a fashion show. When her toxicology screen shows heroin, she is treated for addiction; unfortunately, her symptoms continue after she is weaned off the drugs. Meanwhile, House fights off increasingly bad leg pain which Cuddy and Wilson suppose to be brought on by Stacy’s absence.

House treats a man (Howard Hesseman)^[30] who unknowingly has a seizure and is in need of a new heart. He was admitted by his daughter Amy Errington (Keri Lynn Pratt).^[31] When the transplant committee votes "no," House tries to get one from a dead woman whose organs have also been rejected by the committee. Wilson begins living with House after revealing that his third wife has been cheating on him.

When a man (Eddie Mills)^[33] cannot breathe during sexual role playing with his wife, House questions the motives behind their marriage; Wilson's presence in his house begins to take a toll on him. At the clinic, House treats a husband and wife for herpes as they argue over who first contracted it. House erases a message left on his answering machine from Wilson's apartment hunt.

Melinda (Michelle Trachtenberg), a troubled teenager who is immuno-compromised as a result of medications she must take after a heart transplant, has a severe allergic reaction and goes into shock when her boyfriend visits her. Meanwhile, House and Wilson continue to work out the problems in their new living arrangement, initiating a prank war between the two.

The hospital is hosting an oncology benefit poker tournament when a six-year-old boy (Carter Page)^[36] is brought in exhibiting symptoms identical to those of a patient House had twelve years ago. House is convinced the boy's case is identical and he can predict the course of the young patient's illness, which ended in the first patient's death.

A young woman's (Jayma Mays)^[38] health becomes a question of ethics when she is unable to sleep for ten days. It is not until House discovers she will need a liver transplant that he also uncovers some vital information about her and her partner Max. Meanwhile, Cameron accuses Foreman of plagiarism when an article he authors appears remarkably similar to one of hers.

House wants to call a 15-year-old faith healer's (Thomas Dekker)^[40] bluff, but when the boy is admitted into the hospital he seemingly causes a cancer patient's condition to go into remission. After being diagnosed, the boy refuses brain surgery, but when his condition worsens, House and his staff have to make a decision. Wilson begins sleeping with and living with one of his terminal cancer patients, Grace, who was encouraged by the faith healer.

House is trying to cure a crooked cop (Scott Michael Campbell)^[42] who acts turbulent and laughs uncontrollably, but he and his team are unable to determine the cause. When Foreman starts showing similar symptoms to that of the ill cop, the situation soon becomes deadly serious for everyone involved.

After the police officer dies, Foreman, fearing for his life, contacts his father who rushes to his son's side. Meanwhile, House and the rest of the team are still trying to save Foreman before the disease that killed the officer gets him too. House's team is not allowed to autopsy the officer's body by Cuddy, who is awaiting the evaluation from the CDC in three days. Foreman dreads treatment as his pain increases and a diagnosis eludes the team.

On his way out the door, a man vomits and decides to stay home from work, only to find his wife (Hillary Tuck)^[44] in the bathtub having a seizure and their newborn infant drowning. Chase transfers to the NICU to decompress from working in House's department. Wilson and Cuddy go on a date. Foreman's recovery changes how he relates to the rest of the team.

A 16-year-old Hurricane Katrina victim (Aasha Davis)^[46] suffering from horrifying hallucinations is brought to House by a former bandmate (D. B. Sweeney) who recently discovered the girl is his daughter. Although House fears his friend is being scammed, he takes the case. As he works his way through the girl's lies in order to diagnose and treat her, he is forced to tell a few lies of his own.

When House and his team are working on the diagnosis of a man with a swollen tongue, the husband of a former patient walks into House's office and shoots him in the stomach. House continues to treat his patient from his ICU bed although the shooter (Elias Koteas), who was shot by hospital security and handcuffed to his bed, has become his roommate. When the after effects of the shooting begin to impact House, he starts to question his own ability to diagnose properly. As his patient's body deteriorates, House struggles through self-doubt and must trust his team to find a way to solve the case as well as trying to divide reality from fiction.