The site of today's City of Berkeley was the territory of the Chochen/Huichin band of the Ohlone people when the first Europeans arrived. Remnants of their existence in the area include pits in rock formations, which they used to grind acorns, and a shellmound, now mostly leveled and covered up, along the shoreline of San Francisco Bay at the mouth of Strawberry Creek. Other artifacts were discovered in the 1950s in the downtown area during remodeling of a commercial building, near the upper course of the creek.

The first people of European descent (most of whom were born in America, and many of whom were of mixed ancestry) arrived with the De Anza Expedition in 1776. Today, this is noted by signage on Interstate 80, which runs along the San Francisco Bay shoreline of Berkeley. The De Anza Expedition led to establishment of the Spanish Presidio of San Francisco at the entrance to San Francisco Bay (the Golden Gate), which is due west of Berkeley. Luís Peralta was among the soldiers at the Presidio. For his services to the King of Spain, he was granted a vast stretch of land on the east shore of San Francisco Bay (the contra costa, "opposite shore") for a ranch, including that portion that now comprises the City of Berkeley.

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