The study of poxviruses pioneered the field of vaccinology after Jenner's remarkable discovery that 'vaccination' with the phylogenetically related cowpox virus conferred immunity to the devastating disease of smallpox. The study of poxviruses continues to enrich the field of virology because the global eradication of smallpox provides a unique example of the potency of effective immunization. Other poxviruses have since been developed as vaccine vectors for clinical and veterinary applications and include modified vaccinia virus strains such as modified vaccinia Ankara and NYVAC as well as the avipox viruses, fowlpox virus and canarypox virus. Despite the empirical development of poxvirus-based vectored vaccines, it is only now becoming apparent that we need to better understand how the innate arm of the immune system drives adaptive immunity to poxviruses, and how this information is relevant to vaccine design strategies, which are the topics addressed in this article.