Despite significant advances, there is more work to be done before the international community can be confident that it possesses sufficient protection against any future smallpox threats. The current World Health Organization (WHO)-approved research agenda for smallpox has been tightly focused by the interpretation that research “essential for public health” equates solely to applied research related directly to the development of new antiviral drugs, safer vaccines, and better diagnostics. Despite considerable advances in this direction, we argue that the research agenda with live variola virus is not yet finished and that significant gaps still remain.