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Albert Wesker made his first appearance in the original Resident Evil as the commander of the fictional S.T.A.R.S. law-enforcing task force and leader of the Alpha Team division. He appears through the course of the game as a non-playable character assisting whichever main character the player is controlling (Chris Redfield or Jill Valentine) by making sporadic appearances. As the player goes further into the game, evidences begin to appear in the mansion's underground laboratory implicating Wesker as a member of the Umbrella research staff that worked in the mansion prior to the outbreak. Wesker eventually reveals to the main character that he was ordered by his superiors at Umbrella to lure his S.T.A.R.S. subordinates into the mansion, using them as test subjects against the mutated creatures in the mansion to gather battle data. However, he is either: seemingly killed by the Tyrant creature he unleashes before the final battle; or found dead at the lab's control room next to a self-destruct mechanism.

His next appearance was in [Resident Evil Code: Veronica], where he appears as an agent working for an unnamed secret organization against Umbrella. He reveals in the fictional documentary, Wesker's Report, that he survived his apparent death in the first game by injecting himself beforehand with an experimental virus provided to him by his former colleague William Birkin. The virus brought him back to life, augmenting him with superhuman strength and agility, but at the expense of his humanity. He appears thorough the latter half of Code: Veronica confronting his former subordinate, Chris Redfield and the game's antagonist, Alexia Ashford.

Wesker then appears in Resident Evil Zero and [Resident Evil 4] as a conspirator manipulating events from [behind the scenes]. He is a central character in Resident Evil: The Umbrella Chronicles, where he appears as a playable character in several of the game's scenarios, expanding upon events alluded to in early games, as well as his involvement in Umbrella's downfall after the events of Code: Veronica and his development in [Resident Evil 4]. Wesker is voiced by Richard Waugh in [Resident Evil Code: Veronica], Umbrella Chronicles, [Resident Evil 4], and Resident Evil Zero; and Peter Jessop voices the character in the 2002 remake of the first Resident Evil game.

Wesker's character was adapted by Sony Pictures for the 2007 film Resident Evil: Extinction. Played by Jason O'Mara, this version of Wesker is the head of the Umbrella Corporation. He runs Umbrella's operations from behind the scenes, holding meetings via hologram with his underground board of directors in an undisclosed location in Tokyo, Japan.

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