Illnesses caused by poxviruses have plagued humanity for millennia. The most notable are caused by viruses comprising the orthopoxvirus genus. Smallpox (caused by Variola virus) became the first eradicated disease in 1980. Devotion to smallpox eradication required significant orthopoxvirus research and discovery including vaccine and medical countermeasure development. Here we describe historical and current poxvirus epidemiology, with particular emphasis on orthopoxviruses including Monkeypox virus and Vaccinia virus.