The history of smallpox, from its probable origin 3000 to 6000 years ago to its worldwide eradication in 1978, is a fascinating story. A feared infection, even today, smallpox has caused the deaths of millions of people and disfigured many. This article describes the possible origin of the infection and traces its progress throughout the world. The introduction of inoculation with material from smallpox lesions and vaccination using cowpox virus is described. The World Health Organization's successful smallpox eradication program in the 1960s and 1970s is described. Personal experience of this program in Bangladesh in 1973 is outlined, as is the laboratory escape of the major smallpox virus in Birmingham in 1978. The possible use of the smallpox virus as a biological weapon is discussed.