[1] During the season, House tries to cope with his feelings for his ex-girlfriend Stacy Warner, who, after he diagnosed her husband with acute intermittent porphyria, has taken a job in the legal department of Princeton-Plainsboro Teaching Hospital.

[3] Laura Allen, Yareli Arizmendi, Matthew John Armstrong, Mackenzie Astin, Christine Avila, Marshall Bell, Peter Birkenhead, Tamara Braun, Yvette Nicole Brown, Dan Butler, Scott Michael Campbell, Christopher Carley, Jewel Christian, Michelle Clunie, Aasha Davis, Thomas Dekker, Stephanie Erb, Elle Fanning, Bruce French, Erica Gimpel, Greg Grunberg, Wings Hauser, Taraji P. Henson, Howard Hesseman, Wil Horneff, Ryan Hurst, James Immekus, LL Cool J, William Katt, Mimi Kennedy, Edward Kerr, Elias Koteas, Nathan Kress, Tom Lenk, Ron Livingston, Samantha Mathis, Jayma Mays, Eddie Mills, Cynthia Nixon, Michael O'Keefe, America Olivo, Kip Pardue, Randall Park, Sasha Pieterse, Kristoffer Polaha, Clifton Powell, Keri Lynn Pratt, Cameron Richardson, Charlie Robinson, Ignacio Serricchio, Vicellous Reon Shannon, Allison Smith, Christie Lynn Smith, D. B. Sweeney, Chris Tallman, Michelle Trachtenberg, Hillary Tuck, Alanna Ubach, Stephanie Venditto, Tom Verica, J.R. Villarreal and Julie Warner.

The season gained high Nielsen ratings; "No Reason" was watched by 25.47 million viewers, the show's biggest audience ever at that point.

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.

A famous doctor, Sebastian Charles (Ron Livingston), falls ill when working in Africa, and is sent to House for treatment.

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.

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).

While House and Stacy are in Baltimore, a famed journalist (Michael O'Keefe) collapses in his magazine company's office.

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.

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 fights off increasingly bad leg pain which Cuddy and Wilson suppose to be brought on by Stacy’s absence.

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.

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 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.

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.

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.

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.

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.