Archaeological evidence indicates that Seri occupation of their traditional territory extends well back into prehistoric times. The Seri were in contact with the neighboring Papago, Pima, Yaqui, and Cochimí, and some cultural borrowing occurred. After contact with Europeans, the southernmost band (Guayma) was absorbed fairly quickly into mission life. The island Seri and some coastal people rarely saw Europeans and retained a peaceable and traditional life well into the nineteenth century. The Seri the Europeans came to know were opportunistic groups that migrated into the interior of Sonora and took to raiding and stealing livestock. The mission of Nuestra Señora del Pópulo was founded in 1679 to deal with these trouble-makers, but the Seri had little interest in sedentary life, and the mission was never a success. Seri-European relations worsened and in 1750 erupted in open warfare that raged unabated for twenty years. The nominal peace that followed was soon punctuated by sporadic raids and reprisal campaigns.
After Mexican independence, the pace of hostile encounters quickened, leading to an abortive campaign to exterminate the Seri in 1844. That same year Pascual Encinas established a ranch deep within the Seri range, intending to pacify the Seri with jobs and good treatment. His efforts failed, and in the dozen years of the "Encinas War" beginning in 1855, about one-half of the Seri were killed in skirmishes with Encinas's cowboys. By the late nineteenth century the remaining Seri were shifting between a foraging existence along the coast and islands and eking out a precarious existence on the encroaching ranches. During the 1920s the emerging Mexican fishing industry at Bahía Kino encouraged the Seri to try commercial fishing. A fish cooperative was established in 1938, transforming El Desemboque into the first permanent Seri community. Increasing numbers of North American tourists arriving in the 1960s stimulated a revival of traditional crafts for sale. Although the Seri communities now include a school, a clinic, and an evangelical church, core aspects of Seri culture and social life persist.