Wheatley is first seen early in the game by Chell, attached to a rail on the ceiling. After detaching himself from the rail, he accompanies Chell on a route through the ruined Enrichment Center chambers, using his compatibility with the Center's systems to allow passage through shortcuts. Eventually, they come to GLaDOS' ruined chamber, where she promptly awakens and appears to destroy Wheatley. However, he survives and meets up with Chell later on. During the course of the game, Wheatley aids Chell into escaping from GLaDOS' tests. The two eventually sabotage GLaDOS' turret production line and neurotoxin and later confront GLaDOS herself. A core transference occurs and Wheatley takes over the facility. When he is about to let Chell escape, Wheatley becomes corrupted with power and becomes the game's new main antagonist. Wheatley reconstructs GLaDOS' hardware on to a potato battery and knocks both her and Chell into Aperture Science's old and forgotten test chambers by accident.
After returning from the old test chambers, Chell and GLaDOS learn that Wheatley's actions are causing the facility's reactor to approach a nuclear meltdown. After passing through more test chambers made by Wheatley, he attempts to kill Chell and GLaDOS. After escaping his traps, GLaDOS suggests causing a new core transfer by implanting corrupt Personality Cores into Wheatley.
Chell enters Wheatley's lair to begin the final confrontation of the game. By shutting him down temporarily with bombs, Chell corrupts Wheatley enough to initiate a new core transference, saving the facility from destruction in the progress. However, a stalemate occurs when Wheatley does not agree to transfer himself, and Chell must press the stalemate resolution button to finalize the transfer. However, Wheatley had booby trapped it with explosives, and Chell is flung from the button. Chell survives and launches a portal onto the surface of the Moon, causing both her and Wheatley to be sucked into space. GLaDOS then reacquires her old body and rescues Chell while letting Wheatley be launched into the vacuum of space.
Wheatley is last seen in the epilogue after the end credits, with the Space Core orbiting him, where he wishes he could say he was sorry for all he did to Chell.