Smallpox is an ancient scourge known since the Antiquity. It is caused by a highly contagious airborne poxvirus. This strictly human disease exists in two forms: variola major (Asian smallpox) with mortality of 20–45%, and an attenuated form called variola minor or alatrim with mortality of 1–2%, which only recently appeared in Europe and America towards the end of the 19th century. The first smallpox pandemic was the "Antonine plague", which swept through the Roman Empire in the 2nd century AD, after which smallpox became endemic in the Old World, causing seasonal and regional epidemics in Europe, affecting mostly young children until the 19th century. The discovery of the New World in 1492 and the opening of the African slave trade favored in 1518 the contamination by smallpox of the native Amerindian populations, who were massively decimated during the following centuries. In the absence of any effective treatment, preventive methods were developed from the 18th century. First, variolation was used, a dangerous procedure that consists in inoculating intradermally a small quantity of virus from convalescent patients. In the early 19th century, Edward Jenner popularized the practice of inoculating cowpox, a mild cow disease. This procedure proved to be very effective and relatively safe, leading to the decline of smallpox during the 19th century. In the 20th century, a ten-year WHO vaccination campaign led to the total eradication of smallpox in 1977. During that century, smallpox caused an estimated 300–500 million deaths worldwide. Using molecular approach, it has been discovered that the smallpox virus emerged 3000–4000 years ago in East Africa and is closely related to the taterapox virus from African gerbils and to the camelpox virus, which causes variola in camelids. Today, smallpox virus strains are stored in freezers at the CDC in Atlanta and at the Vector Center in Koltsovo, Siberia. That is why smallpox remains a potential threat to the highly susceptible human species, as a result of an accident or malicious use of the virus as a biological weapon.