In 1791, Father Fermín Lasuén continued the use of Crespi's name when he declared the establishment of La Misión de la Exaltación de la Santa Cruz (also known as Mission Santa Cruz) for the conversion of the Awaswas of Chatu-Mu and surrounding Ohlone villages. It was named 'El Arroyo de la Santisima Cruz, which translates literally as 'The Stream of the Most Holy Cross'. Next morning, the expedition set out again, and Crespi noted that, 'Five hundred steps after we started we crossed a good arroyo of running water which descends from some high hills where it rises. The pueblo of Branciforte was named in honor of Miguel de la Grúa Talamanca, 1st Marquess of Branciforte. Franciscan missionary Juan Crespí, traveling with the expedition, noted in his diary that, 'This river was named San Lorenzo.' (for Saint Lawrence). The party forded the river (probably near where the Soquel Avenue bridge now stands) and camped nearby on October 17, 1769. The first European land exploration of Alta California, the Spanish Portolá expedition led by Gaspar de Portolá, passed through the area on its way north, still searching for the 'port of Monterey' described by Sebastian Vizcaino in 1602. At the time of colonization, the Indigenous people belonged to the Uypi tribe of the Awaswas-speaking dialectical group. The only remnants of their spoken language are three local place names: Aptos, Soquel and Zayante and the name of a native shellfish – abalone. The Awaswas tribe was made up of no more than one thousand people and their language is now extinct. Prior to the arrival of Spanish soldiers, missionaries and colonists in the late 18th century, the area was home to the Awaswas nation of Ohlone people, who lived in a territory stretching slightly north of Davenport to Rio Del Mar. Indigenous people have been living in the Santa Cruz region for at least 12,000 years.

Santa Cruz was founded by the Spanish in 1791, when Fermín de Lasuén established Mission Santa Cruz. The creation of the Santa Cruz Beach Boardwalk in 1907 solidified the city's status as a seaside resort community, while the establishment of the University of California, Santa Cruz in 1965 led to Santa Cruz's emergence as a college town. Following the American Conquest of California, Santa Cruz eventually incorporated as a city in 1866. With the Mexican secularization of the Californian missions in 1833, the former mission was divided and granted as rancho grants.

Soon after, a settlement grew up near the mission called Branciforte, which came to be known across Alta California for its lawlessness. Situated on the northern edge of Monterey Bay, Santa Cruz is a popular tourist destination, owing to its beaches, surf culture, and historic landmarks. As of the 2020 census, the city population was 62,956. Santa Cruz ( Spanish for 'Holy Cross') is the county seat and largest city of Santa Cruz County, in Northern California.

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