Salvia hispanica L., was an important staple Mesoamerican food and medicinal plant in pre-Columbian times. Unlike other Mesoamerican pseudocereal crops such as Amaranthus and Chenopodium, it has received comparatively little research attention. An ethnobotanical review of this Mesoamerican crop plant Salvia hispanica has been undertaken to examine changes in use accompanying Spanish colonization. A comparative analysis of accounts of use from the 16th century codices of Mexico and subsequent publications has revealed subtle changes in medicinal, culinary, artistic, and religious uses. Several hypotheses surrounding changes in use through time and the original use(s) that led to domestication are developed and tested through collection of ethnobotanical data in the highlands of western Mexico and Guatemala. A general decline in ethnobotanical knowledge associated with wild populations coupled with a loss of habitat in some locations has degraded important germplasm and knowledge resources for a species with great economic potential.