Appleseed takes place in the 22nd century, after the non-nuclear Third World War has decimated the Earth. While countries like Great Britain, USA and China have difficulty maintaining order and power, international organizations like the "Sacred Republic of Munma" and "Poseidon" have been established in the aftermath.

Like most cyberpunk novels, the books depict a dystopian future, set in a hypothetical early 21st century where the Soviet Union did not fall, and by the time of the action in the novel, has invaded Western Europe, causing massive disruption and destruction. Their armies are only repelled by the (unseen) use of tactical nuclear weapons, resulting in a stalemate, somewhat like the middle years of World War I.

The main character, Abelard Lindsay, is born in the ancient lunar colony Mare Serenitatis Circumlunar Corporate Republic, into a family of aristocratic Mechanists, but after being sent to the Shaper’s Ring Council, he receives specialized and experimental diplomatic training and gives his loyalty to the Shapers' cause. He, his best friend and fellow Shaper protege Philip Constantine and the beautiful and passionate Preservationist Vera Kelland lead an insurgency against the rulers of the republic, who use Mechanist technology to prolong their lives. The three of them influence the younger generation towards the Shapers' cause in their pursuit of Preservationism, a movement devoted to the preservation of earth-bound human culture. Kelland and Lindsay agree to kill themselves as a political statement, but Lindsay reneges on his suicide pact after Kelland is dead. Constantine attempts to kill Lindsay but instead kills a Mechanist, creating a scandal.

A cop in the future uncovers a global media company's scheme involving harvesting human brains, and decides to join an underground resistance force to take down the company. Coincidentally, he also possesses a “golden brain,” which is invaluable to the company. This book is notable for being the first comic drawn entirely on a computer, specifically a first-generation Apple Macintosh.

A young college student writes a self replicating computer “virus,” programed to survive, that becomes self aware. The program grows and makes mistakes and learns.

Schuyler, a sprinter, one who outruns government particle beam satellites to deliver computer chips to the European black market, becomes a media celebrity and the icon of a new religious cult.

The time is now... but he comes from the Year of Darkness, 2029. He was created to reshape the future by destroying the present. He feels no pity, no pain, no fear. He feels nothing. He is an unstoppable killing machine programmed for murder. He is... The Terminator!