Dr. Gregory House, a drug-addicted, unconventional, misanthropic medical genius, leads a team of diagnosticians at the fictional Princeton–Plainsboro Teaching Hospital in New Jersey.
When Death Row inmate Clarence mysteriously and suddenly collapses after hallucinating, House jumps at the chance to take the case for its difficulty and because it's "cool." Dr. Cameron refuses to treat the patient in protest and feels they should treat a cancer patient because she's more deserving, raising the question: is one life more important than another? Meanwhile, House and Stacy are adjusting to her working at the hospital. As House goes though his diagnostic process, including having a drink or three with his prisoner patient, Dr. Cameron must come to terms with the fact that she just might not be able to help every patient
Andie, a 9-year-old terminal cancer patient, is brought in after suffering from a hallucinogenic episode. Wilson convinces House to take the case, but he and his team struggle to diagnose what caused the hallucination. Andie handles the reality of her terminal medical situation remarkably well - so well that House questions the sincerity of her bravery and considers the possibility it may be a medical symptom. Meanwhile, Andie's request to experience one of life's great "firsts" forces Dr. Chase to make a difficult personal decision. House has an idea of what's causing Andie's medical emergency, but puts the decision in her hands as to whether to take on an extremely risky experimental treatment, one that may end her life even sooner than her terminal illness.
When Cuddy's handyman Alfredo, a young Latino and the sole provider for his family, falls from her roof and develops strange darkened pinkies, Cuddy joins the team in trying to figure out what's wrong with him. Despite everything the team tries, the whole hand becomes infected. As Cuddy struggles with worry and guilt, House and his team are forced to amputate Alfredo's hand so they have more time to diagnose the illness before it kills the patient. However, when Alfredo's other hand starts showing the same symptoms, the doctors look outside the hospital for answers. A trip to the young man's neighborhood helps them understand Alfredo's desire for a better life for his family, and provides a clue as to what might be causing his deadly illness.
When Dr. Sebastian Charles, renowned physician and head of an international organization to fight the spread of tuberculosis among the poor in Africa, is rushed to Princeton Plainsboro Teaching Hospital after collapsing, he immediately determines all the symptoms are from TB. Dr. House has a different opinion and requests additional tests to help determine the cause of his illness. The case begins to get media attention and Dr. Charles sees a chance to further his cause by refusing to submit to any additional tests and take necessary medication in order to gain media exposure for the inadequacies of the medical system for the poor in Africa. As House confronts his patient on live television, his medical condition deteriorates and the team takes over to try to save his life. Meanwhile, Foreman fills in for House in the clinic with disastrous results and Cameron sees eye to eye with Dr. Charles and his cause.
When recent college graduate Carnell drops at a graduation party from internal shocks, he is rushed to Princeton Plainsboro Hospital. With his father Ken at his bedside, it becomes apparent the two have not been truthful with each other in their lives and their major trust issues affect how the medical team gets the information it needs to help solve Carnell's case. Carnell soon develops other symptoms, and House's team suspects it might be from a Spring Break trip out of the country, but have to dig deeper to get all the information. Meanwhile, House has his own issues with his father and is trying unsuccessfully to get out of a dinner engagement with his parents when they arrive in town.
When a famous professional cyclist is brought in after collapsing during a race, House doesn't want to treat him because he thinks he's lying about doing drugs. But when the patient is forthcoming about taking all sorts of performance enhancers and blood-doping drugs, House is definitely intrigued. Cameron is upset the patient is a hero to kids when he is clearly cheating at his sport. She struggles with the ethical dilemma of patient confidentiality and considers going to the media. Meanwhile, House tries to disrupt Stacy and Mark's relationship by attending a group therapy session with Mark.
A gay man with full-blown AIDS collapses in front of House's home and goes into shock. When House discovers the man's father is suffering from symptoms of his own, he must determine if they might be connected and save both their lives. Meanwhile, Cameron faces a potentially life-threatening disease of her own.
House and Chase find themselves in a serious situation after a young mother with stomach pains dies. Months later, Stacy counsels Chase prior to his disciplinary hearing, and must determine whether Chase made a mistake that ultimately led to the patient's death. She soon realizes he is holding something back.
With Foreman as House's supervisor, the team must figure out if a woman who cried wolf too many times is really ill.
While attending his editor's retirement party, a journalist collapses and hits his head on a desk. When he regains consciousness, his sentences are garbled and incoherent, so he is rushed to Princeton Plainsboro Teaching Hospital. With House and Stacy stranded at an airport due to bad weather, the team is forced to solve the case with House helping out over the phone.
While House's staff tries to diagnose a woman whose uncontrollable muscle flailing caused her to crash her car, House and Stacy try to resolve their relationship issues once and for all. Cameron refuses to take her HIV test, wary of the results.
While a severely burned teenager is admitted and his blood tests come back with strange results, House makes himself the guinea pig in his own unofficial tests of a new drug designed to treat migraines to prove a former medical school colleague is wrong about the drug.
House uncovers a startling secret when he treats a teenage supermodel for heroin addiction. Meanwhile, Wilson hopes the increased leg pain in House's leg is an indication his leg nerves are regenerating.
House takes the case of a man who experienced a seizure but wasn't aware it happened. When the man suffers a heart attack and needs a heart transplant, the team races to diagnose a dead woman's illness so they can harvest her heart to save their living patient.
House believes a woman is trying to kill her husband and tries to find the proof to confirm his suspicions. When Wilson moves in with House after separating from his wife, he learns Wilson is a great cook.
Melinda, a troubled teenage girl who is immuno-compromised as a result of the 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.
When a six-year-old boy is brought in with the same symptoms as another patient who died years ago under House's care, House believes the cases are identical and he can predict the course of the boy's illness. Meanwhile, the clinic hosts a poker night to benefit the oncology department.
House has to work fast when a woman comes in with a life-threatening case of insomnia. Meanwhile Cameron is angry at Foreman for stealing an article she worked on.
House treats a 15 year old faith healer, while Wilson feels left out when he finds out House has a weekly poker game.
When a police officer with a gunshot wound to the head and uncontrollable laughter is admitted, House and the team are baffled. When Foreman begins showing the same symptoms, they race to determine the cause of the illness before Foreman's condition takes the same path.
Foreman continues to experience the same progression of symptoms as the police officer. When he realizes he may be facing imminent death, he calls his father who comes to his son's side. As it comes down to a race against time, House believes the solution to the illness is in the police officer's apartment.
A young mother has a seizure while bathing her newborn son and nearly drowns him. House and the team have two cases at one time as they try to save the infant and determine the cause of the mother's seizures.
A 16-year-old Hurricane Katrina victim suffering from hallucinations as a result of the tragedy is brought to House by his former bandmate who recently found out 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 so he can diagnose and treat her, he's forced to tell a few lies of his own.
As House and his team are working on the diagnosis of a man with a giant, swollen tongue, the husband of a former patient walks into House's office and shoots him. House continues to treat his patient from his ICU hospital bed with the shooter, who has been shot by hospital security and hand-cuffed to his bed, as 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 his self-doubt and must trust his team to find a way to solve the case.