When the conquistadors came to conquer the New World they came with a weapon unknown to the Aztecs, smallpox. In their initial invasion the conquistadors were badly beaten by the heavily militaristic Aztecs. After regrouping, months later on their second attack the conquistadors found a civilization devastated by disease. Dead bodies laid in the streets and the Aztecs could mount no defense to the Spanish invasion. An estimated 90% of the population of the Americas succumbed to the disease. After smallpox had brought this devastation to the New World the Spanish, and other European nations were able to conquer and colonize the American Indian Civilizations.

Despite being able to conquer the New World, the Europeans found that they had a very small, and inefficient work force as the American Indians they had enslaved succumbed to European diseases they were not immune to. To find laborers to harvest the natural resources from the colonies the Europeans turned to the West African slave trade. West and North African slaves had already been exposed to European diseases and did not succumb to infection the same way that the American Indians did and were a more economically viable source of labor to power the North Atlantic triangle trade.

Not only was smallpox spread by accident to the natives, it was also used as a means of biological warfare. In North America the British army traded smallpox infected rags with Native American tribes as a way to kill their warriors without having to engage them in combat. This tactic was both effective as it was far reaching as smallpox and other European diseases spread across the American continent decimating Native American populations even before settlers had moved west.