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In 2003, Dr. Serena Kogan (Helena Bonham Carter) of Cyberdyne Systems convinces death row inmate Marcus Wright (Sam Worthington) to sign over his body for medical research following his execution. One year later, the automated Skynet system is activated, becomes self-aware, begins to perceive humans as a threat, and eradicates much of humanity with nuclear weapons in the event known as "Judgment Day".
In 2018, John Connor (Christian Bale) leads an attack on a Skynet base, where he discovers human prisoners and schematics for a new type of Terminator, incorporating living tissue (The T-800). He is the only survivor of the assault after the base is destroyed in a nuclear explosion. Following Connor's departure, Marcus emerges from the base's wreckage and begins walking towards Los Angeles, after taking the clothing from a Resistance soldier, who died in the explosion.
John returns to Resistance headquarters, located aboard a nuclear submarine, and tells General Ashdown (Michael Ironside) of his findings. Meanwhile, the Resistance has discovered a radio signal believed to have been an order to shut down Skynet's machines. Working on this intelligence, the human militia plan to launch an offensive against the Skynet base in San Francisco in four days; in response to an intercepted "kill list" created by Skynet with a plan to terminate the Resistance's command staff. John Connor learns he is second on this list, following Kyle Reese. The Resistance leaders are unaware of Kyle's importance, but John knows Kyle will eventually go back in time and become his father. John returns to his base and meets with his pregnant wife Kate (Bryce Dallas Howard) and his second-in-command Barnes (Common).
Arriving at the ruins of Los Angeles, Marcus sees a T-600 Terminator and yells at it grasping its attention, but before Marcus is killed he is saved by Kyle Reese (Anton Yelchin) and a mute child named "Star" (Jadagrace Berry). Kyle then signs to Star and she sets off a trap for the T-600 that kills it off. After such, Kyle confronts Marcus with a gun and snaps at him about the blood red ribbon on his left arm (symboling Resistance). Marcus snags Kyle's weapon and points it at him instead asking of the year. Kyle tells Marcus about the war between humanity and Skynet and the year. After, Kyle takes Marcus to their base were Marcus finds a broken radio, he fixes it effortlessly and a broadcast appears on it, after hearing John's radio broadcast the three fall asleep. The three leave in search of others in the Resistance. They survive an attack at a gas station; yet Kyle, Star, and several other people are taken prisoner.
Later, two Resistance A-10 airplanes are shot down while trying to intercept a machine transport. Marcus locates downed pilot Blair Williams (Moon Bloodgood) and they make their way to Connor's base, where Marcus is wounded by a magnetic land mine. Attempting to save his life, the Resistance fighters discover that Marcus is, indeed, a cyborg, with a mechanical endoskeleton and a partially artificial cerebral cortex. Although Marcus believes himself to be human, John thinks that Marcus has been sent to execute him and, orders him to be killed. Blair helps Marcus escape. During the pursuit, Marcus saves John's life from Skynet's hydrobots and the two make a bargain: Marcus will enter Skynet's headquarters in San Francisco, to help John rescue Kyle and the other prisoners, if he lets Marcus live.
John pleads with the General to delay the offensive defense, but Ashdown refuses and relieves John of his command. However, the Resistance forces disobey Ashdown's orders and, instead, await John's signal. Marcus enters the base, interfaces with the computer, and disables perimeter defenses so that John can infiltrate the cellblock and release human prisoners. Marcus learns from Skynet (which assumes the form of Dr. Kogan on a screen) that he was created and built to lure John to this base; when the Resistance launches its attack, John will be killed, achieving the goal that Skynet had failed to accomplish so many times before. The radio signal that the Resistance received is revealed to have been a ruse, and Skynet uses it, to track down and destroy the command submarine with the Resistance's leaders aboard.
Marcus tears out the hardware linking him to Skynet and assists John in battling the new T-800 (Model 101) Terminator. Marcus is soon outclassed in strength and temporarily disabled until John revives him, but John is mortally wounded during the fight. Marcus jumps the T-800 when it is distracted and defeats it, while John destroys the Skynet base by rigging together several Terminator fuel cells to explode and detonates them as he, Marcus, Kyle, and Star are airlifted out. Kate attempts to save John's life, but his heart is too badly damaged. Marcus offers his own heart for transplant, sacrificing himself to save John. Recovering, John radios to other Resistance fighters that, although this battle has been won, the war is still not over.