Civilian and military public health agencies are preparing to cope with biological terrorism and warfare through efforts to stockpile vaccines and antibiotics needed to protect against diseases caused by potential biological weapons. Smallpox (Variola major) is a particularly dangerous biological weapon threat because of its clinical and epidemiologic properties. This virus can be manufactured in large quantities, stored for an extended period of time, and delivered as an infectious aerosol. The only commercially approved smallpox vaccine available for limited use in the United States is Wyeth Dryvax. This vaccine is a lyophilized preparation of live Vaccinia virus (VACV). It consists of lyophilized calf lymph containing VACV prepared from live calves. The article discusses adverse events associated with VACV vaccine, developing new VACV vaccines, selection of strain, and selection of cell substrate. It also discusses clinical vaccine trials. Phase 1 trials are primarily designed to evaluate safety and immunogenicity in small groups of closely monitored healthy adult volunteers. One purpose of Phase 2 studies is to identify a preferred vaccine formulation, dose, and schedule for further clinical development in definitive safety and efficacy trials. Phase 3 and beyond may include comparative immunogenicity studies of the new vaccines compared with the licensed vaccines and large-scale trials to provide safety data. The article includes a brief examination of the development of VACV immunoglobulin, the only approved product currently available for treating complications of VACV vaccination. Appendix, references