Monkeypox is a viral disease that resembles smallpox, but unlike smallpox, is acquired from animals. Monkeypox virus is endemic in western and central Africa, where it circulates in unknown animal hosts and emerges periodically to affect humans. The consequences range from asymptomatic infections to severe, fatal illness. This virus also causes illness in nonhuman primates, and outbreaks have been seen occasionally in primate facilities, in various parts of the world. The only outbreak of human monkeypox reported outside Africa occurred in the United States in 2003. The virus entered North America in exotic African rodents imported as pets, and spread to pet prairie dogs, which were highly susceptible to infection. This virus subsequently infected approximately 70 people who had been in contact with these animals. Prompt diagnosis of monkeypox is essential, to prevent this disease from becoming established outside Africa. In addition, it must be distinguished from smallpox, which has been eradicated from human populations but is a potential bioterrorist weapon.