Orthopoxviruses include variola, cowpox, monkeypox and camelpox. Within the orthopoxvirus family variola virus, the causative agent of smallpox, is very transmissible by the air from person to person. All over the world a major population is highly susceptible to this virus. Smallpox has high morbidity and about 30% mortality. Since this disease has not been in occurrence for at least two decades, the diagnosis would be very difficult especially in a major outbreak. Currently, there is a vaccine which can be effective in the first few days of outbreak, but there is no approved drug to treat smallpox. In a post 911 world, we are living in a dangerous phase of terrorism. In a scenario of a possible bioterrorist attack with a poxvirus and with the complexities of the infection, significant attention has been given to the development of effective anti orthopoxvirus agents other than vaccines.