In the mid-1800s, Adam Ewing, an attorney from California, is returning from a business-related voyage to Australia. (It's something involving a will, the executor, and possibly Paul Hogan.) In the Chatham Islands, Ewing meets Dr. Henry Goose, who agrees to treat Ewing's Ailment, which Goose says is a parasite. Ewing assists a stowaway slave, Autua, helping him get a job aboard the ship so that he doesn't get shot or thrown to sharks. Adam Ewing's journal cuts off mid-sentence and we're left with...
In 1931, a bisexual composer named Robert Frobisher concocts a plan to become an amanuensis to famous conductor Vyvyan Ayrs, who lives in Chateau Zedelghem in Belgium. No, that's doesn't mean he's the parasite Ewing was suffering from; it means he's going to help Ayrs record his compositions. At Zedelghem, Frobisher helps Ayrs compose a new symphony, which Ayrs takes all the credit for. Frobisher also spends his time sleeping with Ayrs's wife, Jocasta. In letters to his male lover, Rufus Sixsmith, Frobisher starts getting increasingly frustrated that Ayrs is taking all the credit for their work. He sends his last letter at the end of summer.
In the 1970s, journalist Luisa Rey finds herself trapped in an elevator (and probably in bell bottoms) with Rufus Sixsmith, now a scientist for Seaboard Corp. It's rumored that Seaboard's new nuclear reactor is liable to, well, go nuclear, showering California with radiation, but Seaboard is trying to cover it up.
Luisa is determined to expose Seabord. Alberto Grimaldi, CEO of Seaboard, hires Bill Smoke to murder Sixsmith in his hotel room. Another scientist, Isaac Sachs, has a copy of Sixsmith's report, which he hides in the trunk of Luisa's car. Bill Smoke rams into Luisa while she's speeding away from Swannekke Island in her VW Beetle and sends her plummeting off a bridge.
In the present, editor Timothy Cavendish is pursued by the Hoggins Bros., who want the royalties they feel they are owed from the sales of their brother Dermot's book. Unable to come up with the money, Cavendish asks his brother, Denholme, for a favor. Denny sends Cavendish north, to Hull, where he can hide out for a while.
After a picaresque series of train rides (and one hit off a really strong joint in a public bathroom), Cavendish finds himself in Aurora House, which isn't a hotel, but a nursing home. Cavendish has all his rights and belongings taken away by the nefarious Nurse Noakes. Before he can concoct a plan to escape, he has a stroke.
In the not-so-distant future, Sonmi-451, a fabricant—something like a synthetic human—in Nea So Copros—the new name for the giant world power Korea has become—is being interviewed before her execution. Sonmi has "ascended," which means she's gained a lot more knowledge than fabricants are programmed to have. With the help of Union, an Abolitionist group, Sonmi is taken away from the fast food joint she toils in, Papa Song's, to Taemosan University. When Unanimity enforcers storm the university to take Sonmi into custody, Hae-Joo Im, a grad student who has been helping her educate herself, tells her that he isn't who he says he is—and no, sorry, he isn't Psy.
In the we're-not-sure-how-distant future, Zachry Bailey tells us that the Prescient Meronym, a highly intelligent woman with incredible technology, came to stay with his family in the Nine Valleys of the Big I (the Hawaii of the future). The two climb Mauna Kea, because Meronym is gathering intelligence from the observatories there.
When trading day comes, Kona warriors kill everyone and take Zachry into slavery. Meronym saves him and confesses that all the Prescients, save five, are dead. She had been trying to find a way to save them. Since Zachry's family is dead, too (what a happy coincidence), they escape the island to live on Maui. At the end of his story, Zachry's descendants show us an orison, an egg that plays a video of Sonmi-451.
On the run from Unanimity, Sonmi witnesses the horrors of human nature and the beauty of nature nature—you know, like trees and the ocean and stuff. She agrees to be the figurehead for the Abolitionist movement and is executed for it. Before she is executed, she wants to watch a movie about an old man named Timothy Cavendish.
Cavendish recovers from his stroke, and with the help of Ernie Blacksmith and Veronica Costello concocts a crazy scheme to escape Aurora House. They succeed. With Cavendish Publishing up and running again, Cavendish reads a manuscript, the second half of Half-Lives: The First Luisa Rey Mystery.
Luisa pushes her way out of the sinking VW, but fails to recover the Sixsmith report. After multiple failed murder attempts, Luisa and Joe Napier, the man who once saved her father's life, find a copy of the report aboard the Starfish, Sixsmith's yacht (how many copies of this top-secret report are lying around the place?). Bill Smoke pops up and shoots Napier. Napier shoots Smoke. They both die. So sad. Luisa, however, lives. Thinking she's the reincarnation of Robert Frobisher (we're so not going into that here—check out our "Themes" section), Luisa reads the last eight letters he wrote to Sixsmith back in 1932.
Frobisher starts falling in love with Ayrs's daughter Eva the more he starts falling in hate with her father. Fed up with Ayrs taking all the credit for their mutual work, Frobisher steals Ayrs's pistol and flees Zedelghem. He starts working on his masterpiece, Cloud Atlas Sextet, while writing letters to Eva. She never responds, so Frobisher crashes a party and confronts her... and her fiancé. He thought she loved him, but it was all a misunderstanding. Frobisher finishes his sextet, climbs into the bathtub, and shoots himself. In his second to last letter, he mentions finding the second half of a journal, a journal written by a man named Adam Ewing.
The Prophetess docks at Bethlehem Bay and Ewing mingles with the white locals who are either missionaries or slave traders (it's hard to tell). Back on the ship, Ewing get increasingly more ill despite Goose's treatment of his so-called parasite. It turns out that Goose has been poisoning him all this time. Autua saves Ewing's life and carries him to a nunnery, where he is nursed back to health. Having been saved by a freed slave, Ewing vows to devote his life to the Abolitionist movement. Whew. Got all that?