Prehistoric America was not a disease-free utopia. Tuberculosis, treponemal disease, Chagas disease, and many other pathogens were endemic to populations in different regions of the continent. But the “Columbian Exchange” beginning in 1492 introduced new pathogens to American populations, including smallpox, measles, influenza, and yellow fever. This introduction had devastating consequences for tribes. In some places, death from infectious disease resulted in the depopulation of entire regions, leading to the collapse of social, economic, and political institutions, and the loss of many traditional cultural practices and ways of life.