South San Francisco occupies the basin and portions of the sides of a broad valley formed by the San Bruno Mountains on the north and the Coast Range on the west. Most of the valley faces adjacent San Francisco Bay, affording sweeping vistas, from higher levels and a definite sense of identification with the Bay. South San Francisco has mild winters and dry cool summers. The hills to the west shield the city from much of the fog that prevails in neighboring areas.

Population has tripled since World War II with the opening of such subdivisions as Buri Buri, Winston Manor and Westborough on the slopes west of El Camino. It has grown from 4,411 in 1920 to 61,824 in 2006.  A new BART station opened in June 2003.