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.

With Earth abandoned, humanity resides on Station, an industrialised asteroid run by the sentient corporations of the Pantheon. Under their leadership a war has been raging against the Totality - ex-Pantheon AIs gone rogue. With the war over, Jack Forster and his sidekick Hugo Fist, a virtual puppet tied to Jack's mind and created to destroy the Totality, have returned home. Labelled a traitor for surrendering to the Totality, all Jack wants is to clear his name but when he discovers two old friends have died under suspicious circumstances he also wants answers. Soon he and Fist are embroiled in a conspiracy that threatens not only their future but all of humanity's. But with Fist's software licence about to expire, taking Jack's life with it, can they bring down the real traitors before their time runs out?

Tanta has trained all her young life for this. Her very first mission is a code red: to take her team into the unaffiliated zone just outside InTech's borders and retrieve a stolen hard drive. It should have been quick and simple, but a surprise attack kills two of her colleagues and Tanta barely makes it home alive.

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.

Adan just wants to stay at home with his smart-companion Elegy - phone, friend, confidante, sex toy. But when his mother flees to Europe and joins a cult, leaving him penniless, he has to enlist in the army. Sentient robots are invading America, but it seems Adan has a surprising ability to survive their attacks. He has a purpose, even if he doesn't know what it is. And in the far future, war between a hivemind of Ais and the remnants of humanity is coming to its inevitable end. But one woman has developed a weapon which might change the course of the war. It's just a pity she's trapped in an inescapable prison on a hivemind ship.

An ex-corporate enforcer, Hakan Veil, is forced to bodyguard Madison Madekwe, part of a colonial audit team investigating a disappeared lottery winner on Mars. But when Madekwe is abducted, and Hakan nearly killed, the investigation takes him farther and deeper than he had ever expected. And soon Hakan discovers the heavy price he may have to pay to learn the truth.