Smallpox is an acute contagious disease caused by variola virus, causing at least two million deaths every year before 1970. After the introduction of smallpox vaccine and the global immunization campaign launched by World Health Organization (WHO), the global eradication of smallpox was achieved in 1980. Smallpox was the first virus to be eradicated from nature by humankind. Nevertheless, the highly contagious and fatal nature of smallpox and the advancement of technology increase the possibility of using smallpox as a bioterrorism agent by terrorist groups. Therefore, many of countries have stockpiles of smallpox vaccine to respond to the threat of biological warfare. In particular, after the 2001 attacks, the United States considered smallpox vaccine as preparedness goods and put significant resources for the advance of production, quality and safety of smallpox vaccine. Although it is not clear whether the actual use of smallpox as a bioweapon would occur or not, we have to be prepared beforehand for risk reduction in bioterrorism threat and damage.