The Spanish empire sponsored the earliest missionary activity in the West, when the Franciscans established missions in California in 1541 and New Mexico in 1581. Friar Junipero Serra founded nine California missions between 1769 and 1782, beginning with Mission San Diego. Franciscan missions converted Indians to Catholicism-sometimes voluntarily, sometimes by force-and taught them farming and handicraft skills. They also stimulated the economic development of the region by creating ranching, agricultural and manufacturing enterprises, which often relied on the forced labor of natives.

The first Protestants to establish missions west of the Mississippi River were the Methodists, who built their first mission in Oregon's Willamette Valley in 1834. Presbyterians arrived in Oregon Country two years later. Although these first missionaries failed to convert many Indians, they did provide a stimulus for future settlement since they established prosperous farms and sent glowing reports back east about the fertile lands of the Northwest.