San Francisco is first seen in the episode "Smug Alert!". It's shown to be the smugiest city in America, because everyone there drives Hybrids, which are the leading cause of smug. Cartman thinks that everyone in San Francisco are hippies. When Gerald Broflovski buys a Hybrid, he starts to think that everyone in South Park are ignorant, so he and his family move to San Francisco. He tells Stan Marsh that they might return if he can get people to drive Hybrids. Stan does so, but when all the people of South Park starts driving Hybrids, a giant problem occures. A huge cloud of smug is created over South Park, making it the second smugiest city in America. Stan is then told that South Park might have a chance of surviving the deadly smug cloud, but San Francisco doesn't have a snowball's chance in hell. The episode ends with a total destruction of San Francisco and severe damage to South Park. Before it was destroyed it was revealed that most children in San Francisco do drugs, as they are not capable of dealing with their parent's excessive smugness.
San Francisco was again mentioned in "Whale Whores", suggesting the city had been rebuilt.
In the song "You and Cthulhu" played in "Mysterion Rises" with Eric Cartman and Cthulhu flying through the air, Cthulhu destroys San Francisco, along with hippies, and a synagogue; everything Cartman hates.