 The Tepehuán and their neighbors may have been reduced in population by more than 80 percent by the epidemics, from a pre-Columbian population of more than 100,000 to fewer than 20,000, of which the Tepehuán may have been one-half of this total

During the Chichimeca war (1550–1590) the Tepehuán remained neutral although urged by the Chichimecas to join them in resistance to Spanish expansion.The Spanish failed to defeat the Chichimeca militarily and instituted a new policy called "peace by purchase" in which Catholic missionaries would be a major tool in pacifying hostile and semi-hostile Indians.Indians were to be supplied with food and tools and resettled into towns.