Smallpox was a devastating disease that decimated human populations for centuries, and its eradication in 1980 was a monumental achievement for the global health community. Since then the remaining known strains of its causative agent, variola virus, have been contained in two World Health Organization (WHO)-approved repositories. In 1999, the World Health Assembly (WHA) debated the issue of destroying these remaining strains. Arguments were presented on the need to retain the live virus for use in additional important research, and the decision to destroy the virus was deferred until this research could be completed. In that same year, the Institute of Medicine (IOM) convened a consensus committee to explore scientific needs for the live virus. In the ten years since the first IOM report, the scientific, political, and regulatory environments have changed. In this new climate, the IOM was once again tasked to consider scientific needs for live variola virus. The committee evaluated the scientific need for live variola virus in four areas: development of therapeutics, development of vaccines, genomic analysis, and discovery research.