We reviewed historical data from 2 smallpox outbreaks in Liverpool and Edinburgh during the early and middle years of the 20th century to assess their contribution to developing modern strategies for response to a deliberate release of smallpox virus. Reports contemporaneous to these outbreaks provide detail on the effectiveness of public health interventions. In both outbreaks, extensive contact tracing, quarantine, and staged vaccination campaigns were initiated, and the outbreaks were controlled within 15 months and 3 months, respectively. In Edinburgh, the number of fatalities associated with vaccination exceeded the number of deaths from the disease. In Liverpool, ambulatory, vaccine-modified cases and misdiagnosis as chickenpox resulted in problems with outbreak control. The relatively slow spread of smallpox, as exemplified by the report from Liverpool, allowed for effective implementation of targeted intervention methods. Targeted surveillance and containment interventions have been successful in the past and should be explored as alternatives to mass vaccination.