Five centuries ago the European invaders arrived to the New World. They carried with them what turned out to be their main allies in the conquest of the continent: smallpox, measles and influenza viruses. In an attempt to recompose the process of dissemination of such diseases, a systematic review of the biomedical and historical literature was performed, to investigate how the Spaniards first, and the British later, used mainly smallpox to undertake a biological warfare against the American Indians, which eventually meant the biggest population catastrophe that America has never suffered in all its history