In the novel's somewhat dystopian world, human personalities can be stored digitally and downloaded into new bodies, called sleeves. Most people have cortical stacks in their spinal columns that store their memories. If their body dies, their stack can be stored indefinitely. Catholics have arranged that they will not be resleeved as they believe that the soul goes to Heaven when they die, and so would not pass on to the new sleeve. This makes Catholics targets for murder, since killers know their victim will not be resleeved to testify. A UN resolution to alter this legal position forms one strand of the novel's plot, to allow the authorities to sleeve a deceased Catholic woman temporarily to testify in a murder trial.

Carl Marsalis is a selectively bred human ("genetic variant") known as a "Thirteen", characterized by high aggression and low sociability. Bred to serve in a military capacity, Thirteens were later confined on reservations or exiled to Mars. Carl, having won by lottery the right to return from Mars, works covertly, tracking down renegade Thirteens.

The story begins with the introduction of Iris, a female Blade Runner, and the best in her unit. Meyer - her boss - tells her that the blade runner division is in danger; far fewer replicants are coming to Earth, and thus the economic value of the blade runners is dropping, giving the risk of a "reorganisation". Meyer gives Iris the assignment to track down an owl - an extremely rare, real owl, named Scrappy. Iris is skeptical, since if the owl is real (and thus not a replicant) the case seems to be nothing to do with the blade runners, but she accepts the job anyway.

Some 30 years after Altered Carbon, Takeshi Kovacs is now serving in Carrera's Wedge, a mercenary organisation which joins a corporate war on a distant colony, Sanction IV, and fights the rebellion against the corporate-sponsored government. While having his latest body repaired after a disastrous campaign, Kovacs is approached by pilot Jan Schneider, who is looking for protection for an expedition to exploit a Martian artefact discovered just before the war broke out. "Martian" artefacts have been known for many years at this point, one of them being featured in Altered Carbon. Later it is realised that the "Martians" were not from Mars, but were a technologically advanced species that left artefacts on many planets, including Mars and Kovacs' home world.

Seven years after the events of Neuromancer, strange things begin to happen in the Matrix, leading to the proliferation of what appear to be voodoo gods (hinted to be the fractured remains of the joined AIs that were Neuromancer and Wintermute). Two powerful multinational corporations, Maas Biolabs and Hosaka, are engaged in a battle for control over a powerful new technology (a biochip), using hackers and the Matrix as well as espionage and violence.

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.