Mixe territory originally extended from the Río Nexapa to Coatzacoalcos and from Villa Alta to the Isthmus of Tehuantepec. At the beginning of the fourteenth century, Mixe continuity on the Gulf Coast was disrupted by a series of Central Mexican (Pipil) and Maya invasions. They were also forced to cede the western isthmus region to the Huave, and Nexapa to the Zapotec. Under a succession of kings, the Mixe waged war against the Zapotec, the Mixtec, and their allies. Despite their numerical superiority, these groups, seeking tribute and territory, were unable to defeat the Mixe. By 1522, however, the Mixe had become tributary subjects of the Zapotee lord of Tehuantepec. The Spaniards and their Indian allies were unable to defeat the Mixe in several expeditions launched against them. Although the Spaniards were able to subdue a few settlements in 1531, by 1560 the Mixe had not been conquered. The final pacification of the Mixe nation was carried out by Dominican friars, who established parishes and centers of evangelization throughout the region. Cruel treatment and excessive tribute resulted in serious insurrections in 1570, 1660, and 1661. Following the initial expeditions of the Conquest, there were no large movements of Spanish settlers into the region. In 1660 a decree ordering the consolidation of the dispersed settlements into larger nucleated towns, in order to administer and missionize the Mixe more effectively, resulted in the decimation of the population from typhoid, smallpox, and influenza epidemics.
Although forced labor drafts had been discontinued by 1650, tribute in goods was drawn from the Mixe region as late as 1789. In 1780 the Dominicans were replaced by Spanish secular priests, who were expelled after the War of Independence. Thereafter, the region was served by only one priest, who came to the villages for the annual religious feast. In the latter part of the twentieth century, the Mixe region has undergone marked economic, political, and religious change brought about by the construction of roads, the advent of state development agencies, and renewed Catholic missionary activity.
Contemporary Mixe culture is an amalgam of indigenous, Spanish-colonial, and regional Oaxaca traits. The retention of the Mixe language and territory was instrumental in preserving many native religious beliefs and practices. Spanish influence is most evident in village layout and housing construction, religion, livestock, and the use of metal tools. Slash-and-burn agriculture and digging-stick technology is complemented, in some villages, by European plow agriculture. Regional influence, such as the presence of the dress and music of the Isthmus in eastern Mixe villages, is also a factor. The construction of roads in the region has greatly facilitated the introduction of new foods, industrial goods, and the replacement of thatched roofs with corrugated-metal ones.