Since the 16th century, the Mexican territory underwent various political, demographic, environmental and cultural changes. During these vertiginous changes, many unknown microorganisms were imported into the country, and others flourished due to both global and local armed movements. In this article, the import and dissemination routes are documented, as well as the morbidity and mortality of the most important epidemics that have caused the death of millions of Mexicans. Some significant historical events that occurred in parallel to these outbreaks are described, from the Spanish conquest to modern times. The article also presents the transformations that the Mexican health systems implemented in each historical moment and how they faced health challenges.