The book consists of six nested stories, whereof each is read (or observed) by a main character of the next. The first five stories are each interrupted at a pivotal moment. After the sixth story, the other five stories are closed, in reverse chronological order, and each ends with the main character reading or observing the chronologically previous work in the chain. Each story contains a document, movie, or tradition that appears in a previous story.
The Pacific Journal of Adam Ewing (Part 1)
The first story begins in the Chatham Islands in the mid-nineteenth century where Adam Ewing, a guileless American notary from San Francisco during the California Gold Rush, awaits repairs to his ship. Ewing witnesses a Moriori slave being flogged by a Maori overseer. During the punishment, the victim, Autua, sees pity in the eyes of Adam Ewing and smiles. Later Ewing ascends a high hill called Conical Tor and stumbles into its crater, where he finds himself surrounded by faces carved into trees. Reasoning that those who carved the faces must have had egress from the crater, he escapes. As the ship gets underway, Dr. Goose, Ewing's only friend aboard the ship, examines the injuries sustained on the volcano and Ewing also mentions his chronic ailment. The doctor diagnoses it as a fatal parasite and recommends a course of treatment. Meanwhile, Autua has stowed away in Ewing's cabin; and Ewing breaks this news to the Captain, to whom Autua proves himself a first class seaman, whereupon the Captain puts him to work for his passage to Hawaii.
Letters from Zedelghem (Part 1)
The next story is set in Zedelghem, near Bruges, Belgium, in 1931. It is told in the form of letters from Robert Frobisher, a recently disowned and penniless bisexual young English musician, to his lover Rufus Sixsmith, after Frobisher journeys to Zedelghem to become an amanuensis to the reclusive once-great composer Vyvyan Ayrs, who is dying of syphilis and nearly blind. Soon, Frobisher produces Der Todtenvogel ("The Death Bird") from a basic melody that Ayrs gives him. It is performed nightly in Kraków, and Ayrs is much praised. Frobisher takes pride in this and has begun composing his own music again. Frobisher and Ayrs' wife Jocasta become lovers, but her daughter Eva remains suspicious of him. Frobisher sells rare books from Ayrs' collection to a fence, including half of The Pacific Journal of Adam Ewing, and has suspicions that Dr. Goose is poisoning Adam. Once, Ayrs has Frobisher write a song inspired by a dream of a "nightmarish cafe", deep underground, wherein "the waitresses all had the same face", and ate soap. As the summer comes to an end, Jocasta thanks Frobisher for "giving Vyvyan his music back", and Frobisher agrees to stay until next summer.
Half-Lives: The First Luisa Rey Mystery (Part 1)
The third story is written in the style of a mystery/thriller novel, set in the fictional city of Buenas Yerbas, California, in 1975, with Luisa Rey, a young journalist. She meets Rufus Sixsmith in a stalled elevator, and she tells him about her late father, one of the few incorruptible policemen in the city, who became a famous war correspondent. Later, when Sixsmith tells Luisa his concern that the Seaboard HYDRA nuclear power plant is not safe, he is found dead of apparent suicide. Luisa believes that the businessmen in charge of the plant are assassinating potential whistle-blowers. From Sixsmith's hotel room, Luisa acquires some of Frobisher's letters. Another plant employee gives her a copy of Sixsmith's report, and then the plane he is on explodes. Before Luisa can report her findings on the nuclear power plant or the murders, a Seaboard-hired assassin who has been following her forces her car — along with Sixsmith's incriminating report — off a bridge.
The Ghastly Ordeal of Timothy Cavendish (Part 1)
The fourth story is comic in tone, jarring after the previous story, and is set in Britain in the present day, wherein Timothy Cavendish, a 65-year-old vanity press publisher, flees the brothers of his gangster client, whose book is experiencing high sales after the murder of a book critic. They threaten violence if monetary demands are not met. Timothy's own brother, exasperated by his frequent previous pleas for financial aid, books him into a menacing nursing home. Timothy signs custody papers thinking that he is registering into a hotel, where he can stay until his personal and financial problems can be solved. Learning the truth that he is here indefinitely without the ability to leave or communicate with anyone, and subject to the staff's complete control, he attempts flight but is stopped by a security guard and confined. Timothy briefly mentions reading a manuscript entitled Half-Lives: The First Luisa Rey Mystery, but is not impressed by the prospective author's manuscript. Timothy settles into his new surroundings, while still trying to plot a way out. One day, he is struck by a seizure, just as the chapter ends.
An Orison of Sonmi~451 (Part 1)
The fifth story is set in Nea So Copros, a dystopian futuristic state in Korea, derived from corporate culture. It is told in the form of an interview between Sonmi~451 and an "archivist" recording her story after her arrest and trial. Several small spelling and grammatical changes are made, to represent the change in language. Sonmi~451 is a fabricant waitress at a fast-food restaurant called Papa Song's. Clones grown in vats are revealed to be the predominant source of cheap labor. The "pureblood" (natural-born) society retards the fabricants' consciousness by chemical manipulation, using a food she refers to as "Soap". After twelve years as slaves, fabricants are promised retirement to a fabricant community in Honolulu. In her own narration, Sonmi encounters members of a university faculty and students, who take her from the restaurant for study and assist her to become self-aware, or "ascended"; she describes watching The Ghastly Ordeal of Timothy Cavendish as a pre-Skirmishes film (wherein the "Skirmishes" are a major global disaster or war that destroyed most of the world except Nea So Copros (East Asia), which foreshadows "The Fall" in the subsequent chapter "Sloosha's Crossin", in which Nea So Copros, and most of humanity's technological ability, have ended in disaster; the destroyed areas are identified as "deadlands" full of disease, ruins, and radioactive contamination). During the scene when Cavendish suffers his seizure, a student interrupts to tell Sonmi and her rescuer Hae-Joo Im that Professor Mephi, Hae-Joo's professor, has been arrested, and that policy enforcers have orders to interrogate Hae-Joo and kill Sonmi on sight. Hae-Joo then reveals that they are members of an antigovernment rebel movement called Union.
Sloosha's Crossin' an' Ev'rythin' After
The sixth story occupies the central position in the novel and is the only one not interrupted, wherein Zachry, an old man, tells a story from his youth, speaking an imagined future English dialect. It is gradually revealed that he lived in a post-apocalyptic society on the Big Island of Hawaii. His people, called the valley folk, are peaceful farmers but are often raided by the Kona tribe, who are cannibalistic slavers. Zachry is plagued by moral doubts stemming from his wrongly blaming himself for his father's death years ago. Zachry's people worship a goddess called Sonmi and recall a 'Fall' in which the civilized peoples of Earth — known as the 'Old Uns' — were destroyed, and left the survivors to primitivism. Big Island is occasionally visited and studied by a technologically sophisticated people known as the Prescients, whereof a woman called Meronym, who has come to learn their ways, is assigned to live with Zachry's family. Zachry becomes suspicious of her, believing that her people are gaining trust before doing harm, and sneaks into her room, where he finds an 'orison': an egg-shaped device for recording and holographic videoconferencing. Later, Zachry's sister Catkin is poisoned by a scorpion fish, and he persuades Meronym to break her people's rules and give him medicine. When Meronym later requests a guide to the top of Mauna Kea volcano, Zachry reluctantly guides her there to the ruins of the Mauna Kea Observatories. Here, Meronym explains the orison and reveals Sonmi's history (introduced in the prior chapter). Upon their return, they go with most of the valley-folk to trade at Honokaa; but Zachry's people are attacked and imprisoned by the Kona who are conquering the territory. Zachry and Meronym eventually escape, and she offers to let Zachry come with them, but he tells her he cannot leave. Wounded, he is taken to a safer island. The story ends with Zachry's child recalling that his father told many unbelievable tales; whereas this one may be true because he has inherited Zachry's copy of Sonmi's orison, which he often watches, even though he does not understand her language.
An Orison of Sonmi~451 (Part 2)
Guided by Hae-Joo Im, Sonmi goes in disguise to a ship, where she witnesses retired fabricants butchered and recycled into soap, the fabricant food source. The rebels plan to raise all fabricants to self-awareness and thus disrupt the workforce that keeps the corporate government in power. They want her to write a series of abolitionist Declarations calling for rebellion. She does, knitting in the themes of greed and oppression first brought up in the diary of Adam Ewing, and this final tale agrees with Ewing's ideas that if greed and corruption are allowed to take over, with the selfish overwhelming the weak successively, it will bring down all.
She is then arrested in an elaborately filmed government raid and finds herself telling her tale to the archivist. Sonmi believes that everything that happened to her was instigated by the government to encourage the fear and hatred of fabricants by purebloods. She thinks that Union is run by the government to attract malcontents so that they can be watched and controlled. However, even knowing that she will be executed, she feels that her show trial and well publicized Declarations will be inspirational nonetheless to those who will one day change things. Her last wish before her death is to finish watching Cavendish's story, which she is presumed to do.
The Ghastly Ordeal of Timothy Cavendish (Part 2)
Having mostly recovered from his mild stroke, Cavendish meets a small group of residents also anxious to escape the nursing home: Ernie, Veronica, and the extremely senile Mr. Meeks. He assists their conspiracy to trick Johns Hotchkiss, a fellow patient's grown son, into leaving his car vulnerable to theft. They seize the car and escape, stopping at a bar to celebrate their freedom. They are nearly recaptured by Hotchkiss and the staff but are rescued when Mr. Meeks exhorts the local drinkers to come to their aid.
It is thereafter revealed that Cavendish's secretary Mrs. Latham blackmailed the gangsters with a video-record of their attack upon his office, allowing him to return to his former life in safety. Subsequently, Cavendish obtains the second half of Luisa Rey's story intending to publish it, and he considers having his own recent adventures turned into a film script.
Half-Lives: The First Luisa Rey Mystery (Part 2)
Rey escapes from her sinking car but loses the report. When her newspaper is bought by a subsidiary of Seaboard, she is fired, and Luisa believes that they no longer see her as a threat. She orders a copy of Robert Frobisher's obscure Cloud Atlas Sextet which she has read about in his letters and is astonished to find that she recognizes it, even though it is a very rare piece. However, Smoke the assassin still pursues her and lures her with a copy of Rufus Sixsmith's report about the power plant. Joe Napier, a security man who knew her father, comes to her rescue, and Smoke and Napier kill each other in a gun fight. Later, Rey exposes the corrupt corporate leaders to the public. At the end of the story, she receives a package from Sixsmith's niece, which contains the remaining eight letters from Robert Frobisher to Rufus Sixsmith.
Letters from Zedelghem (Part 2)
Frobisher continues to pursue his work with Ayrs while developing his own Cloud Atlas Sextet. He finds himself falling in love with Eva, after she confesses a crush on him, though he is still having an affair with her mother. Jocasta suspects this and threatens to destroy his life if he so much as looks at her daughter. Ayrs also becomes more bold with his plagiarism of Frobisher, now demanding he compose full passages, which Ayrs intends to take credit for. Ayrs also informs him that if he leaves, Ayrs will have him blacklisted claiming he raped Jocasta. In despair, Frobisher leaves anyway, but finds a hotel nearby working to finish his Sextet and hoping to be reunited with Eva. He convinces himself that they are being kept apart from her parents, but when he finally manages to talk to her he realizes that the man she was talking about being in love with was her Swiss fiancé. Mentally and physically ill Frobisher ultimately decides, with his magnum opus finished and his life now empty of meaning, to kill himself. Before committing suicide in a bathtub, he writes one last letter to Sixsmith and includes his Sextet and The Pacific Journal of Adam Ewing.
The Pacific Journal of Adam Ewing (Part 2)
Ewing visits the island of Raiatea, where he observes missionaries oppressing the indigenous peoples. On the ship, he falls further ill and realizes at the last minute that Dr. Goose is poisoning him to steal his possessions. He is rescued by Autua and resolves to join the abolitionist movement. In conclusion (of his own journal and of the book), Ewing writes that history is governed by the results of vicious and virtuous acts precipitated by belief: wherefore "a purely predatory world shall consume itself" and "The devil take the hindmost until the foremost is the hindmost", and imagines his father-in-law's response to his becoming an abolitionist, as a warning that Adam's life would amount to one drop in a limitless ocean; whereas Ewing's proposed reply is: "Yet what is any ocean but a multitude of drops?"