MaddAddam picks up where Oryx and Crake and The Year of the Flood (which take place in parallel time) leave off. The story begins with the Crakers coming upon Ren, Toby, Amanda, Jimmy (whom they know as Snowman). Toby is the primary protagonist and is followed to the Cobb House by the Crakers and the others.
Zeb isn't present at Cobb House because he, and some other men, have been looking for Adam One, the leader of God's Gardeners, in the hope that he has survived. Zeb evades kidnapping and, as he tells his story to Toby, we learn that he is the half-brother of Adam. We learn that a woman forager called Swift Fox is also attracted to Zeb and this puts a strain on the new relationship between Zeb and Toby. Amanda learns that she is pregnant and it is probably because of the one of the sadistic Painballers who had raped her (The Year of the Flood).
Later, Toby succeeds in communicating with Pilar, the Eve to the Gardeners' Adam, and learns to create an abortifacient for Amanda. Toby also begins to get close to a Craker child called Blackbeard, whom she teaches how to read and write.
In the final chapters, there's a battle between the Painballers and the others and the Painballers are finally killed (something Toby was unable to do at the beginning of the book). Eventually Zeb, Toby, and Jimmy die too. However, the future is less bleak than it seemed at first. The Painballers have been defeated for good. The women who had sex with the Crakers have managed to give birth, thus re-starting a different kind of life. The Crakers and the genetically modified pigs are able to live in relative harmony. The novel ends when Blackbeard becomes the keeper of humanity, partly because of all he learned from Toby.