The team treats a performance artist Afsoun Hamidi who deliberately made herself ill, to turn the diagnostics department into her new masterpiece documentary. House must decide which of her symptoms are real and which are self-inflicted. The team questions whether treatments are necessary and if they are unwitting participants in creating a piece of her art. As the case progresses, House vows to change 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.

When House discovers that the experimental drug he's been using causes fatal tumors, he decides to attempt to excise them himself. However, he can't complete the surgery and needs Cuddy's help. Meanwhile, Thirteen's friend from prison and relapsed drug user, Darrien, arrives at her apartment unannounced, needing medical care after being stabbed. With her friend unwilling to go to the hospital, Thirteen enlists Chase's assistance when the friend loses sensation and movement in her arm. Also, Taub receives some unexpected news that could change his life.

After losing a bet with Wilson over a boxing match, House believes his fighter has an underlying medical condition that cost him the fight. House presses the boxer for more information to prove his case and attempts to breathe new life into the losing fighter's career. Meanwhile, he leaves his team alone to help a bomb scientist who suffered a seizure. They also suspect House may be experimenting with a new drug to relieve his leg pain.

After suffering partial paralysis while searching for a long-lost love, lottery winner Cyrus Harry arrives at Princeton Plainsboro for treatment by House and the team. The patient also suffers from multiple types of cancer. The team must figure out if his new millionaire lifestyle is making him sick. Meanwhile, Cuddy's mother, Arlene, threatens to sue the hospital for malpractice over her treatment, jeopardizing both Cuddy's and House's medical licenses. Foreman and Chase make a bet over who is repressing the uglier side of their personality more.

Masters faces a career crossroads on her last day as a medical student and struggles with the choice to continue on the path to become a surgeon or to accept the rare opportunity to join House's team officially. Meanwhile, the team treats a 16-year-old girl who inexplicably collapsed days before embarking on an ambitious sailing tour around the globe. Despite the patient's life-changing diagnosis, the patient's family insists on getting her back on the seas in time for her potentially record-breaking launch. But to the team's surprise, including House, Masters makes a bold decision regarding the patient's treatment.

House discovers that Thirteen has been in prison and meets her when released. He has a dual purpose for being there: he wants to know what she did to end up in jail, and he needs her help to win a local spud-gun shooting contest. Meanwhile, the team treats a science teacher suffering from severe respiratory illness. Taub tries to get back into the dating scene but retreats to his old habits.

A young homeless man who is a former drug addict is found in a park showing signs of olfactory impairment and horrific scars and burn marks on his chest. With an uncertain identity and the patient's severely worsening conditions, the team looks to the patient's records and family history to understand his detachment. Meanwhile, Cuddy reveals her guilt to Wilson about breaking up with House.

The team treats a professional bull rider after a bull attacks him. The team must determine the causes behind the patient's disappearing symptoms and seizures, concluding he needs risky open-heart surgery. The team enlists House's advice from outside the hospital as he attends to issues unrelated to the case. Meanwhile, Masters develops a crush on the patient, surprising Taub.

Tension reaches new heights when Cuddy faces sobering news that forces 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. Sensing the teen's troubled emotional and mental state, Taub turns to the patient's personal life for clues and uncovers disturbing home videos that could put the lives of his peers in danger. Meanwhile, Cuddy remains hopeful that House will be fully present when she needs him most, and a series of dreams, including a musical scene choreographed by Mia Michaels, provide glimpses into her life and her relationship with House.

After breaking out in a severe rash triggered by caustic chemical exposure at his blue-collar job, a patient is admitted. As the team treats him, they discover that he has led his wife to believe he is still maintaining his once-lucrative real estate career. Meanwhile, Cuddy is honored with an award and needs House to be at the charity event for support. But his attendance is threatened when his patient's battle to survive forces him to question his practice and happiness. Chase and Masters teach each other a lesson in forging meaningful personal and professional relationships.

House participates in a school's Career Day and breaks a few rules by sharing explicit medical stories. Waiting outside the principal's office, he meets two fifth-grade students who assess House's relationship woes and try to help him understand how his selfish antics prevent him from showing Cuddy how he really feels.

When a waitress with a perfect memory suffers temporary paralysis, her older sister visits her in the hospital, which triggers high stress levels and even more health complications. Meanwhile, Foreman volunteers to help Taub prepare for a medical examination, and House, determined to help Wilson get back in the dating scene, discovers Wilson's secret new companion.

After complaining about unusual symptoms, Cuddy's mother, Arlene, is admitted to Princeton Plainsboro. Still, stubborn Arlene insists that House be removed from the case, forcing House to develop non-conventional - and illegal - means to treat his patient.

A teenage military trainee at a juvenile offender training camp suffers peculiar symptoms after enduring an intense training course, and mysteriously, his drill sergeant is soon admitted for similar symptoms. Sensing Cuddy's stress over her daughter Rachel's enrollment at a prestigious preschool, House secretly prepares Rachel for observations and reveals a soft spot for the toddler.

When a man puts his life on the line to save a stranger who fell onto the subway tracks, he emerges from the dramatic scene miraculously unscathed but then suddenly collapses. Meanwhile, House tries to avoid Cuddy's birthday dinner with her opinionated mother, Arlene, and Taub draws unexpected attention when his face graces billboards advertising the hospital.

Science and faith are called into question when a patient is admitted to the hospital after he starts coughing up blood while being crucified. Meanwhile, Taub questions his wife Rachel about her relationship with an infidelity support group member and the team attends a co-worker's wedding where Wilson's relationship with Sam takes an unexpected turn.

After a 200-year-old medicine jar found on an off-shore shipwreck shatters in a teenage girl's palm, she is admitted to Princeton Plainsboro for symptoms closely linked to smallpox. Meanwhile, Wilson and Sam comfort a 6-year-old chemotherapy patient, who prompts them to examine their relationship. House makes a dangerous decision that puts his life in jeopardy. 

It's election season, and in the midst of a tight campaign, an incumbent New Jersey senator's campaign manager falls ill with liver failure and temporary paralysis. Cuddy pushes House to add a female doctor to his team by hiring brilliant third-year medical student Martha Masters in Thirteen's absence.

After a newborn experiences inexplicable breathing problems and liver failure, House and the team look at the baby's mother, Abbey's, own medical history for possible clues. Meanwhile, following Cuddy's directive, House challenges Foreman and Taub to hire a female doctor to join the team. When Cuddy asks House to babysit her daughter, both House and Wilson learn a few hard lessons in parenting.

Princeton Plainsboro admits a patient named Margaret McPherson suffering severe and uncontrollable vomiting. House and the team make unexpected discoveries about her identity as they assess her symptoms. Meanwhile, a visit from House's massage therapist forces House and Cuddy to confront the reservations in their relationship. Also, House tasks Chase with hiring a replacement for Hadley; he hires Dr. Kelly Benedict who later quits. 

Alice, the author of a popular children's book series, inexplicably suffers a seizure moments before she attempts to take her own life. The Princeton Plainsboro team faces the challenges of evaluating her underlying medical conditions and unstable psychological state. House, a fan of the books, puts her on psych hold but deals with a patient more eager to die rather than be cured. 

Meanwhile, House worries that he will lose Cuddy because they have nothing in common. House and Cuddy double-date with Wilson and his ex-wife Sam.

When Della, a seemingly healthy and active 14-year-old, suddenly collapses during a skateboarding exhibition, House and his team struggle to diagnose her condition and reassure her parents, who already have to cope with their son's terminal illness. House and Cuddy face the challenge of handling their romantic relationship at work.

House and Cuddy explore the ramifications of their feelings and attempt to make a real relationship work. Meanwhile, Princeton Plainsboro is left without a neurosurgeon on-site due to a colleague's illness, threatening the hospital's accreditation as a Level 1 Trauma Center. As the team attempts treatment to get their sick colleague back to work, they discover there is more to the illness than they initially suspected and turn to House for direction. Instead, House remains elusive, leaving the team on its own.