The first inhabitants of the geographic region which would eventually become San Leandro were the ancestors of the Ohlone people, who arrived sometime between 35 BC.
The Spanish settlers called these natives Costeños or "coast people" and the English-speaking settlers called them Costanoans.
It 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; The city is particularly noted for the South San Francisco hillside sign on Sign Hill, which rises to the north of the city, with large white letters that proclaim "South San Francisco, The Industrial City".
The sign, a tribute to the city's industrial past, is listed on the National Register of Historic Places.
The larger, Rancho San Antonio, approximately 44,000 acres (18,000 ha) was given to another Spanish soldier Don Luis Maria Peralta in 1820.
Beginning in 1855, two of Estudillo's sons-in-law, John B.
Lab Corp employees in Alamance County participated in the Ronald Mc Donald House Sport a Shirt, Share a Night fundraiser event.
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South San Francisco lies north of San Bruno and San Francisco International Airport in the Colma Creek valley south of Daly City, Colma, Brisbane, and San Bruno Mountain; east of Pacifica and the hills of the northern Coast Range lying along the San Andreas Fault; west of the waters of San Francisco Bay.
Locals often refer to the town as South City, in much the same way that San Francisco is called "The City." Belying the name, South San Francisco does not touch on San Francisco, with either Brisbane, Colma, or Daly City lying between them.