Monkeypox virus is an orthopoxvirus that is genetically distinct from other members of the genus, including Variola virus, Vaccinia virus, Ectromelia virus, Camelpox virus, and Cowpox virus. It was first identified as the cause of a pox-like illness in captive monkeys in 1958. In the 1970s, human infections occurred in Central and Western Africa clinically indistinguishable from smallpox. In contrast with Variola virus, however, Monkeypox virus has a wide range of hosts, which has allowed it to maintain a reservoir in wild animals. Human monkeypox was first recognized outside Africa in 2003 during an outbreak in the US that was traced to monkeypox virus-infected rodents imported from West Africa. Today, monkeypox is regarded as the most important orthopoxvirus infection in human beings since the eradication of smallpox. There is currently no proven treatment for human monkeypox, and its potential as an agent of bioterrorism is discussed.