The utility of poxviruses as expression vectors was first described in the early 1980s. Since then, poxviruses have been widely used as vaccine delivery platforms in human and veterinary medicine. The main features that make poxviruses excellent antigen delivery platforms and vaccine vectors are their large genome size with the presence of multiple immunomodulatory genes, the tolerance for large heterologous gene insertions, and their ability to induce cellular and humoral immunity. Initial attempts were focused on engineering vaccinia virus to express heterologous genes. Later, the potential of other poxviruses including avipoxvirus, parapoxvirus, and swinepox viruses as vectors was also explored with promising results. To address the safety concerns related to wild-type poxviruses, several highly attenuated, replication-defective strains have been developed mostly by serial passages in cell culture. Most of the recombinant poxviruses developed to date have targeted insertional inactivation of the thymidine kinase (TK) gene, in which the heterologous gene is inserted in the TK locus in the poxvirus genome. In recent years, other immunomodulatory genes have also been used to generate safer and multivalent poxvirus-vectored vaccine candidates. Poxvirus vectors have been shown to be very effective in heterologous prime-boost immunization regimes, where poxvirus vectors are used in combination with other killed or DNA vaccine formulations. To date multiple poxvirus-vectored vaccines have been licensed for use against a variety of animal pathogens including rabies virus (RabV), avian influenza virus (AIV), canine distemper virus (CDV), and West Nile virus (WNV).