As the world prepares to celebrate the quincentennial events surrounding the discovery of the New World by Christopher Columbus in 1492, a particular interest regarding the influence of epidemic infectious diseases on the history of the conquest of America has emerged. Contrary to popular belief, it was not the European guns or fierce soldiers that conquered the native Americans, but instead it was the common childhood illnesses brought from the Old World by the European conquistadors. Diseases such as smallpox, measles, and typhus annihilated most of the American native populations. Devastating epidemics resulted throughout the New World. We will review the consequences of introducing new infectious agents into a nonimmune population, discuss the major pathogens that were imported from the Old World, and focus on how these diseases may have affected the aboriginal depopulation of the Americas.