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The people most closely tied to the Hispano-Mexican settlers in San Diego's mission valley called themselves Kumeyaay. The Kumeyaay themselves were a large band spread throughout what is present-day San Diego county and into northern Baja California, comprising two divisions with dialects of the same language. To the north, from Escondido to the coast lived the Ipai or northern Diegueño. The Tipai or Diegueño Kumeyaay lived in present-day Mission Valley and down south into northern Baja California.

The Kumeyaay lived in hundreds of small semi-permanent "rancherías" or village camping spots, migrating with the seasons to the mountains during the annual harvest of acorns and grain grasses which were their staple foods. They were very successful in maintaining a dense population in comparison to other regions of North America. Probably between nineteen and twenty-five thousand Kumeyaay people resided in San Diego at the time of first Spanish contacts in 1769.