With the arrival of Europeans in the Western Hemisphere, Native American populations were exposed to new infectious diseases, diseases for which they lacked immunity. These communicable diseases, including smallpox and measles, devastated entire native populations. In this article, we focus on the effect of smallpox on the Native Americans from the 15th through the 19th centuries. Among the "new" infectious diseases brought by the Europeans, smallpox was one of the most feared because of the high mortality rates in infected Native Americans. This fear may have been well-founded, because the Native Americans were victims of what was probably one of the earliest episodes of biological warfare. Fortunately, they were also major beneficiaries of early vaccination programs. Thus, the arrival of smallpox and the decline of the Native American populations are inexorably linked, as the history summarized here illustrates.