Thousands of years ago, variola virus (smallpox virus) emerged and began causing illness and deaths in human populations, with smallpox outbreaks occurring from time to time. Thanks to the success of vaccination, the last natural outbreak of smallpox in the United States occurred in 1949. In 1980, the World Health Assembly declared smallpox eradicated (eliminated), and no cases of naturally occurring smallpox have happened since.

Smallpox research in the United States continues and focuses on the development of vaccines, drugs, and diagnostic tests to protect people against smallpox in the event that it is used as an agent of bioterrorism.