While working on his graduate thesis in geography in the Sierra Nevada, Ish is bitten by a rattlesnake. As he heals from the bite, he gets sick with a disease that looks like measles and he moves in and out of consciousness. He recovers and makes his way back to civilization, only to discover that most people died from the same disease. He goes to his home in Berkeley. In the city near his home Ish meets few human survivors– a man drinking himself to death, a couple who seem to have lost their sanity, and a teenage girl who flees from him as someone dangerous. He comes across a dog (a beagle bitch), friendly and eager to join him. The dog, which he names Princess, swiftly adopts Ish as her new master and sticks by him for much of the book. He sets out on a cross-country tour, traveling all the way to New York City and back, scavenging for food and fuel as he goes. As he travels, he finds small pockets of survivors, but has doubts about humanity's ability to survive the loss of civilization.
He returns to his home in California after reading Ecclesiastes (and realizing he had been throwing his life away), to find a woman, Emma (Em), living nearby. They agree to consider themselves married and have children. They are gradually joined by other survivors. Over time the electricity fails and the comforts of civilization recede. As the children grow, Ish tries to instill basic academics by teaching reading, writing, arithmetic, and geography, but he is largely unsuccessful due to a lack of interest by the others.
Many children are born in these years and among them is Joey, Ish's youngest and favorite son. Joey is very similar in nature to Ish, as he demonstrates innate intelligence and a curiosity about the world before the epidemic. This leads Ish to believe that Joey is the key to the future.
Twenty-two years later, the community flourishes. The younger generation adapts easily to the more traditional world. They come to have a better grasp of the natural world than the adults, and when running water fails, the younger generation comes to the rescue, knowing where flowing streams may be found. Ish turns his attention from ecology to his newly forming society. One thing that he notices is that the children are becoming very superstitious. One day Ish asks for his hammer, an antique miner's tool he found in the mountains, which he habitually carries around, and finds the children are afraid to touch it. It is a symbol for them of the old times. The long-dead "Americans" are now like gods—and Ish is too.
As years go by, the community begins to grow corn and make and play with bows and arrows. Ish presides at meetings, his hammer being a symbol of his status. He is given respect, but his ideas are ignored by the younger men.
Ish spends most of his elderly life in a fog, unaware of the world. Superstition has set in; the tribe has reverted to a traditional lifestyle, hunting with dogs and bow and arrow. Occasionally the fog in his mind lifts. During one such time, he finds himself aware of his great-grandson Jack, who stands before him. Jack shows him that the bow and arrow have become more reliable than the gun, whose cartridges do not always work. Ish realizes that the former civilization is now completely gone. But he also wonders if the new world is that much worse off than the old world, and finds himself hoping that the new world will not rebuild civilization and its mistakes.