The area has long been inhabited by the Kumeyaay Native American people. The first European to visit the region was Juan Rodríguez Cabrillo. Cabrillo was Portuguese (his name in Portuguese was Joao Rodrigues Cabrilho) but he was a long-term resident of Spanish America. He was commissioned by Viceroy Antonio de Mendoza to continue the explorations of California. In 1542, Cabrillo discovered San Diego Bay, which he named San Miguel. He went ashore, probably in the Ballast Point area of Point Loma. His landing is re-enacted every year at the Cabrillo Festival sponsored by Cabrillo National Monument.
The bay and the area of present-day San Diego were given their current name sixty years later by Sebastián Vizcaíno when he was mapping the coastline of Alta California for Spain in 1602. The explorers camped near a Native American village called Nipaguay and celebrated mass in honor of San Diego de Alcala (Saint Didacus of Alcalá). California was then part of the Viceroyalty of New Spain under the Audiencia of Guadalajara.
In 1769, Gaspar de Portolà and his expedition founded the Presidio of San Diego (military post), and on July 16, Franciscan friars Junípero Serra, Juan Viscaino and Fernando Parron raised and 'blessed a cross', establishing the first mission in upper Las Californias, Mission San Diego de Alcala. Colonists began arriving in 1774. In the following year the Kumeyaay indigenous people rebelled against the Spanish. They killed the priest and two others, and burned the mission. Father Serra organized the rebuilding, and two years later a fire-proof adobe and tile-roofed structure was built. By 1797 the mission had become the largest in California, with a population of more than 1,400 presumably converted Native American "Mission Indians" relocated to and associated with it.