Partly in response to their family's objections to cousins getting married, and partly to flee a pesky ghost, José Arcadio Buendía, his wife Úrsula, and a bunch of friends set off to found a new town, Macondo.
The Buendía family is important in the town, and soon enough, Macondo is large enough to need some way of contacting the outside world. After Úrsula finds a route to neighboring towns, Macondoans are forced to the live with the consequences: government intervention and the arrival of many new, non-idealistic people.
Seeing that the government is corrupt, Colonel Aureliano Buendía sets off to wage war against the Conservatives in power. The civil war is useless and endless. Eventually he gives up the fight and signs a humiliating peace agreement with his enemies.
A banana company comes to Macondo. At first it seems to create a lot of prosperity, but it's actually abusing and taking advantage of its workers. When they strike, they are viciously gunned down. Macondo, meanwhile, thinks that none of this ever happened. As it forgets its past, it doesn't seem to have much of a future.
Every character we meet in the novel is killed or dies in some grotesque way, ending with the last Buendía – a baby with a pig's tail who is eaten by fire ants. The town itself is annihilated by a hurricane.