The Colonial Defense Forces (CDF) learn that one of their top consciousness transfer scientists, Charles Boutin, has turned traitor and sparked an unprecedented alliance between three other species to wipe out humanity. While investigating Boutin's clumsy attempt to fake his own death, the CDF discovers that Boutin had successfully stored a copy of his consciousness in a computer. The colonial Special Forces, nicknamed "The Ghost Brigades," create a CDF soldier body with Boutin's DNA to try to implant the copy of Boutin's consciousness into the new brain, to learn where Boutin has escaped to and what his intentions really are. After the attempt seemingly fails, the soldier (named Jared Dirac, after Paul Dirac) becomes a private in the Special Forces and is assigned to a platoon commanded by Jane Sagan. On the off chance that Boutin's consciousness does emerge, Sagan and her superiors are determined to keep an eye on Jared. Time passes and an experience that reminds Dirac of Boutin's daughter Zoe leads Boutin's consciousness to emerge. Jared slowly becomes more and more like Boutin while losing his own personality traits, but retains his individuality and his strong moral opposition to Boutin's philosophy and actions. When the extent of Boutin's treachery becomes known, it's clear there will be some difficult choices required to stop Boutin's alliance with the Rraey, Eneshan and Obin.

A mission to the moon where Boutin is helping the Obin build their consciousness transfer technology, led by Sagan and Dirac, is catastrophically compromised by Boutin's use of a backdoor to disable the soldiers' BrainPals and render many of them catatonic. Dirac is interrogated by Boutin, who decides to transfer his own consciousness into Dirac's body in an attempt to infiltrate and destroy the Colonial Union. The transfer succeeds, ending Dirac's consciousness. Dirac is able to posthumously neutralize Boutin by leaving a Trojan horse in a BrainPal message, oxidizing his body's smart blood and killing him. Boutin's daughter Zoe is retrieved by the survivors of the mission, including Sagan. At the end of the book, Sagan is offered retirement in order to keep her from disclosing sensitive information she received from Boutin; she accepts and retires with her future husband John Perry, adopting Zoe. The Obin proceed to sign a treaty with the CDF that ends hostilities.

All of the colonial defense forces are given genetically altered bodies with all sorts of upgrades, with the special forces getting the most. These soldiers are born into these bodies, and only through their BrainPal do they know what to do. This universe is a hostile place and these upgrades are the bare minimum the CDF can give them just to hold their own. Travel in the universe is done by skip drive, an instantaneous means of transportation. Jane Sagan, Harry Wilson and John Perry are the only primary characters returning from Old Man's War.

The Ghost Brigades introduces the following races:

• Eneshan: Human-sized insectoid race descended from a termite-like creature. Nominally allies with the CDF. Society is hierarchical, matriarchal and highly tribal, with much inter-tribal conflict.
• Obin: Evolved on the moon of a gas giant, they were given intelligence but not individual consciousness by another alien species, the Consu. The Obin are described as a hermaphroditic species that resemble a cross between a spider and a giraffe. They generally do not interact with other races, except to attack; they are brutal, merciless, and unrelenting when they do.
• Gameran: These are actually a subspecies of humans, designed by the CDF to live natively in space. They appear similar to large rock turtles and can hide easily among asteroids, planetary rings, and other bodies or satellites. They also have the first generation of BrainPal that is entirely organic.