Prospects for the eradication of smallpox are now highly encouraging. With the cessation of man-to-man transmission, the question of possible animal reservoirs of smallpox becomes increasingly important. During the period 1970-1975, 20 cases of a smallpox-like disease were detected in smallpox-free areas of tropical rain forest in West and Central Africa. Epidemiological and virological investigations revealed that the disease was caused by an animal poxvirus termed monkeypox virus, a member of the orthopox virus group. The disease spread with difficulty even among susceptible close contacts and does not appear to be sufficiently transmissible to permit continuing infection to become established in man. During the investigations, four orthopox viruses termed whitepox viruses were isolated from rodents and monkeys. The isolates were not distinguishable from variola virus with currently available laboratory techniques, but there is no evidence so far that viruses of this group have infected man. Although there is now substantial and accumulating evidence that there is no animal reservoir for smallpox, continued surveillance and studies in West and Central Africa are warranted.