Vectors based on vaccinia virus (VACV), the vaccine used to eradicate smallpox, are currently popular candidates for vaccination against numerous infectious diseases including malaria and AIDS. Although VACV induces robust cellular and humoral responses, enhancing the safety and efficacy of these vectors remains an important area of research. VACV expresses a plethora of proteins that inhibit the host innate immune response to infection and recent work has demonstrated that the removal of some of these genes from the virus enhances vaccine efficacy. One example is a recombinant VACV Western Reserve (WR) strain lacking the C6L gene (vΔC6). C6L encodes an immunomodulatory protein C6 which acts as an inhibitor of interferon regulatory factor 3 activation (1). Intradermal vaccination of mice with vΔC6 provided better protection against challenge with a lethal dose of WR compared to wild-type virus, despite attenuation. Increased protection was not due to improved humoral responses, but instead correlated with enhanced cytotoxic activity of T cells one month post-vaccination (2). Current research is now focussed on gaining a mechanistic understanding of how the removal of genes that modulate the innate immune response positively impacts the formation of immune memory, with the hope of not only improving the safety and efficacy of VACV as a vaccine vector, but also allowing us to identify ways to design more immunogenic vaccines.