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The Santa Clara Valley has been home to the Tamyen group of the Ohlone people since around 4,000 BC. The Tamyen spoke Tamyen language of the Ohlone language family. With the Spanish colonization of California, the majority of the Tamyen came to inhabit Mission Santa Clara de Asís and Mission San José.

California was claimed as part of the Spanish Empire in 1542, when explorer Juan Rodríguez Cabrillo charted the Californian coast. During this time, California and Baja California were administered together as Province of the California (Spanish: Provincia de las California). For nearly 200 years, the Californias were sparsely populated and largely ignored by the government of the Viceroyalty of New Spain in Mexico City. Only in 1769 was Northern California finally surveyed by Spanish authorities, with the Portolá Expedition.

In 1776, the Californias were included as part of the Captaincy General of the Provincias Internas, a large administrative division created by José de Gálvez, Spanish Minister of the Indies, in order to provide greater autonomy for the Spanish Empire’s lightly populated and largely ungoverned borderlands. That year, King Carlos III of Spain approved an expedition by Juan Bautista de Anza to survey the San Francisco Bay Area, in order to choose the sites for two future settlements and their accompanying mission. First he chose the site for a military settlement in San Francisco, for the Royal Presidio of San Francisco, and Mission San Francisco de Asís. On his way back to Mexico from San Francisco, de Anza chose the sites in Santa Clara Valley for a civilian settlement, San Jose, on the eastern bank of the Guadalupe River, and a mission on its western bank, Mission Santa Clara de Asís.