Aaron Cross (Jeremy Renner) is a member of Operation Outcome, a U.S. Defense Department black-ops program that enhances the physical and mental abilities of field operatives through pills referred to as "Chems". Cross is deployed to Alaska for a training assignment, where he must survive certain activities and traverse rugged terrain to arrive at a remote cabin. The cabin is operated by an exiled Outcome operative, Number Three (Oscar Isaac), who, upon arrival, informs Cross that he broke the previous mission record by two days.Meanwhile, the Blackbriar and Treadstone programs are publicly exposed, leading the FBI and the U.S. Senate Select Committee on Intelligence to investigate the director of the Central Intelligence Agency Ezra Kramer (Scott Glenn), Deputy Director Pamela Landy (Joan Allen), Blackbriar supervisor Noah Vosen (David Strathairn), and Treadstone clinical researcher Dr. Albert Hirsch (Albert Finney). Kramer requests help from Eric Byer (Edward Norton), a retired U.S. Air Force colonel responsible for overseeing the CIA's clandestine operations. Byer discovers potentially damaging video on the Internet in which the lead researchers for Treadstone and Outcome appear together at professional functions in public. To prevent the Treadstone investigation from finding and revealing Outcome's top-secret scientific advances, Byer decides to end Outcome and kill its agents. He sees this sacrifice as acceptable because the government has already separately initiated next-generation "beta programs", including the super-soldier program LARX.Byer deploys an unmanned drone to Alaska to destroy Number Three's cabin and kill both him and Cross. Cross hears the drone's approach and leaves the cabin moments before a missile destroys it with Number Three inside. Cross continues to be tracked and escapes the immediate area to higher ground. As the drone is entering its second attack run, he quickly tapes a Mylar thermal blanket and metal bowl to his thigh, causing the signal used to track and target him to be lost. He subsequently fires on the drone with his sniper rifle, causing it to crash.Realizing that his superiors have ordered his assassination, Cross removes a tracking device implanted in his thigh and force-feeds it to a member of a wolf pack hunting him. A second drone soon kills the wolf, and Byer assumes that Cross has been killed. Byer engineers the death of other Outcome assets through poisoned yellow Chems. To erase the Treadstone-Outcome link, Hirsch dies of an apparent heart attack before he can testify before the U.S. Senate. Byer also tries to eliminate Outcome's private research lab by chemically brainwashing scientist Dr. Donald Foite (Zeljko Ivanek) into committing a murder-suicide. The only survivor is geneticist Dr. Marta Shearing (Rachel Weisz).Cross has to take pills at regular intervals & his cache of pills is lost in the drone attack. He treks his way back to the only place he can source his pills from, the lab that gave them to him in the first place.When an expert team of CIA assassins attacks Shearing at her house, she is rescued by Cross, who convinces her to help him. He saw press coverage about her survival of the murder-suicide at the lab and sees her as his last link to get the Chems so he can maintain his enhanced self and alleviate his Chem withdrawal. Shearing reveals that without his knowledge, Cross has already been genetically modified to retain the physical benefits conferred by the green Chems without continuous consumption (a process called "Viraling off"), but still requires regular consumption of the blue Chems, which improves intelligence. Cross and Shearing travel to Manila, Philippines, where the Chems are manufactured, to help him viral off of the blue Chems. The Chems are essentially viral manifestations & Viraling off is the process in which the stem virus is directly planted in the body to induce genetic mutation to make the viral effects permanent.While en route, Cross confides in Shearing that he is really Kenneth J. Kitsom, a U.S. Army Private First Class reportedly killed by a roadside bomb during the Iraq War. He admits that he had below-average intelligence that the Chems enhanced, and fears the loss of his enhanced intellect. Byer tracks Cross and Shearing to Manila but is too late.In Manila, Cross and Shearing bluff their way into the factory that produces the pills, locate the live virus "stems" from which the pills are made, and initiate the viral-off process for the blue Chems. Byer contacts the factory's security staff, but Cross and Shearing manage to escape. Byer orders LARX-03 (Louis Ozawa (as Louis Ozawa Changchien)), a chemically brainwashed super-soldier, to kill them. They take shelter in a flophouse, where Shearing helps Cross recover from the Flu-like symptoms of Viraling off. During the night, he hallucinates about his initiation into Outcome, under Byer's supervision.Later, presumably the following morning, police surround the flophouse while Shearing is away buying medicine. She screams out a warning to Cross, who escapes and rescues Shearing from pursuing police officers. Cross and Shearing steal a motorcycle, pursued by both the police and LARX-03. After a lengthy chase through the streets and marketplaces of Manila, the police lose them and LARX-03 fatally crashes into a warehouse pillar. Shearing and Cross slide off their damaged motorcycle and are rescued by a Filipino boatman. They pay him a gold Rolex watch (which Cross stole earlier from the Chem factory's supervisor), to take them out of the country. The movie ends with them on a boat among many islands.