The first story begins in the Chatham Islands in New Zealand during the mid-nineteenth century, where Adam Ewing, a guileless American lawyer from San Francisco, awaits repairs to his ship.

It is an epistolary, told through a collection of letters from Robert Frobisher, a recently disowned and penniless young English musician, to his lover Rufus Sixsmith.

Frobisher journeys to Zedelghem to become an amanuensis to the reclusive once-great composer Vyvyan Ayrs, who is dying of syphilis and nearly blind.

Ayrs asks Frobisher to write a song inspired by a dream of a "nightmarish cafe", deep underground, wherein "the waitresses all had the same face" and ate soap.

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 protagonist Luisa Rey, a young journalist.

She meets the elderly 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, after Sixsmith tells Luisa his concern that the Seaboard HYDRA nuclear power plant is not safe, he is found dead of apparent suicide.

The fifth story is set in Nea So Copros,[2] a dystopian state in twenty-second century Korea, derived from corporate culture.

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).

On the Big Island of Hawaii after a great societal collapse, the Valley Folk are peaceful farmers who worship a goddess called Sonmi.

Zachry Bailey is plagued by moral doubts stemming from blaming himself for his father's death and the kidnapping of his brother years prior.

When Meronym later requests a guide to the top of Mauna Kea volcano, Zachry reluctantly agrees, citing his debt to her for saving his sister Catkin from poisoning.

They climb to the ruins of the Mauna Kea Observatories, where Meronym explains the orison Zachry found in her room and reveals Sonmi's history (as introduced in the prior chapter).

Any leftover "reclaimed proteins" from the butchered fabricants are used to produce food that purebloods unknowingly consume at fast-food type restaurants.

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.

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.

She orders a copy of Robert Frobisher's obscure Cloud Atlas Sextet, which she has read about in his letters to Rufus Sixsmith, and is astonished to find that she recognizes it, even though it is a rarely published piece.

Mentally and physically ill Frobisher ultimately decides, with his magnum opus finished and his life now empty of meaning, to kill himself.

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.

Both Ichiyanagi and Lennon were husbands of Yoko Ono, and Mitchell has said this fact "pleases me ... though I couldn't duplicate the pattern indefinitely.

[4] Mitchell said that Vyvyan Ayrs and Robert Frobisher were inspired by English composer Frederick Delius and his amanuensis Eric Fenby.

[13] The BBC's Keily Oakes said that although the book's structure could be challenging, "David Mitchell has taken six wildly different stories ... and melded them into one fantastic and complex work.

"[18] The Washington Post's Jeff Turrentine called it "a highly satisfying, and unusually thoughtful, addition to the expanding 'puzzle book' genre.

"[20] Marxist literary critic Fredric Jameson found its new, science fiction-inflected variation on the historical novel now "defined by its relation to future fully as much as to past.

F&SF reviewer Robert K. J. Killheffer praised Mitchell's "talent and inventiveness and willingness to adopt any mode or voice that furthers his ends," but noted that "for all its pleasures, Cloud Atlas falls short of revolutionary.

[34][5] Mitchell has said of the book: Literally all of the main characters, except one, are reincarnations of the same soul in different bodies throughout the novel identified by a birthmark ... that's just a symbol really of the universality of human nature.

[36] According to Mitchell, who authorized both editions, the differences emerged because the editor assigned to the book at its US publisher left their job, leaving the US version un-edited for a considerable period.