In many episodes, House is seen playing Metroid: Zero Mission on his Game Boy Advance SP. In Season 1, Episode 3, he hands his Game Boy Advance SP to a clinic patient while he talks to Wilson; in the same episode, he's seen dying to a Chozo Statue in Zero Mission - something impossible in the game, as the statue heals you every time you morph into its hands.

In Mob Rules, another first-season episode of House (which first aired on March 22, 2005), a judge orders House to treat a mob informant. House does so under protest, but even when the patient recovers, he figures something is wrong with him and wants to keep treating him. When he butts heads with Vogler over the treatment of the patient, Vogler spends two days fighting with Cuddy over House's continued employment, resulting in Cuddy having to make a terrible compromise to keep House at the hospital. Meanwhile, House figures out someone on his team is keeping Vogler informed and takes steps to try to confirm who it is while taking intermittent breaks to play Metroid Prime Hunters on his brand new Nintendo DS.

Lines in the Sand is a 3rd season episode of House which first aired on September 26, 2006. In the episode, House is drawn to the case of an autistic boy because he can't communicate well enough to give House any clues as to his underlying health problems. In one scene, the autistic patient is seen playing this game on his PSP.

In the fifth season episode "Dying Changes Everything", the team treats the assistant of a powerful woman, and Thirteen starts to see something of her nature in the patient's subordination to her employer. In grief over Amber's death, Wilson contemplates resigning from the hospital. When House reacts by telling him to get over it, their friendship is strained to the point where Cuddy has to be called in to do the equivalent of couples counseling. However, when push comes to shove, it appears that House may have to choose between his friendship with Wilson, the life of his patient, or his job at Princeton-Plainsboro.

The fifth season premiere used the natural break between seasons to naturally build the tension over the ramifications of Amber's death. When we return to PPTH, just as much fictional time as real-time has passed, and Wilson is still at an impasse. Like House, we've been anticipating what would happen after House and Wilson parted without a word.

Certainly, this isn't the only episode where Hilson, the eternal bromance, has been threatened. However, it's one of the ones that posed the greatest challenge to the relationship between the two men. Probably far too late, Cuddy tries to mediate between the two, but her motives are far from clear - and Wilson knows it. Ostensibly, she wants to keep Wilson at the hospital. However, her hidden agenda is that she knows that it's unlikely that she will be able to handle House without Wilson's help. Throughout the series, it's usually been Wilson suggesting ways to Cuddy to keep the brakes on House's more excessive behaviors, and neither of them has been above using House's relationship with Wilson to manipulate the hospital's resident mad genius - who is seen playing Ninja Gaiden II on a patient's Xbox 360 during one of the episode's main scenes.

In Perils of Paranoia, a Season 8 episode, a district attorney appears to suffer from a heart attack while cross-examining a witness. The initial diagnosis is hyper-anxiety, but the team finds an arsenal at the patient's home and start to believe that his extreme paranoia is a physical symptom. Wilson becomes convinced that House is hiding something at 221B Baker Street, which leads to an epic battle of wits between the two men wherein House refers to the Pokèmon Arceus as a God of Creation and claims to have the legendary beast on his team.