The action takes place in 2023–2025 in Galveston, Texas; Atlanta, Georgia; Grenada, an island on the northeast coast of South America; Singapore; and Africa. Protagonist Laura Webster, mother of three-month-old Loretta, works as a public relations employee for Rizome, a global corporation of economic democrats. Together with her husband David they run the Lodge, a resort for Rizome workers on the island of Galveston. The action sets off when Rizome organizes a conference between itself and three data havens - EFT Commerzbank of Luxembourg, The Young Soo Chim Islamic Bank and Grenada United Bank - in the Lodge. After the first day of the conference Winston Stubbs, the Grenadan representative, is assassinated. The organization which admits to killing him calls itself "F.A.C.T." (Free Army of Counter-Terrorism). Rizome decides to send Laura with her husband and baby to Grenada on a diplomatic mission to prove that Rizome had nothing to do with the murder.

Welcome to Los Angeles...where anger, hunger and disease run rampant, and life and hope are strictly rationed. This is Jonny's world. He's a street-wise hustler, a black-market dealer in drugs that heal the body and cool the mind. All he cares about is his own survival. Until a strange plague turns L.A. into a city of death--and Jonny is forced to put everything on the line to find the cure. If it can be found on earth...

Taking place eight years after the events of Count Zero and fifteen years after Neuromancer, the story is formed from several interconnecting plot threads, and also features characters from Gibson's previous works (such as Molly Millions, the razor-fingered mercenary from Neuromancer). One of the plot threads concerns Mona, an innocent young prostitute who has a more-than-passing resemblance to famed Simstim superstar Angie Mitchell. Mona is hired by shady individuals for a "gig" which later turns out to be part of a plot to abduct Angie.

The Culture--a humanoid/machine symbiotic society--has thrown up many great Game Players. One of the best is Jernau Morat Gurgeh, Player of Games, master of every board, computer and strategy. Bored with success, Gurgeh travels to the Empire of Azad, cruel & incredibly wealthy, to try their fabulous game, a game so complex, so like life itself, that the winner becomes emperor. Mocked, blackmailed, almost murdered, Gurgeh accepts the game and with it the challenge of his life, and very possibly his death.

Set in 2030–2031, ten years after the events of Software, Wetware focuses on the attempt of an Edgar Allan Poe-obsessed bopper named Berenice to populate Earth with a robot/human hybrid called a meatbop. Toward this end, she implants an embryo in a human woman living on the Moon (Della Taze, Cobb Anderson's niece) and then frames her for murder to force her to return to Earth. After only a few days, she gives birth to a boy named Manchile, who has been genetically programmed to carry bopper software in his brain (and in his sperm), and to grow to maturity in a matter of weeks.