Poxviruses represent a heterogenous group of DNA viruses that have been utilized to express a multitude of foreign genes. An improved understanding of the virally encoded genes involved in regulating the host immune response has led to specially designed vectors with varying levels of immune induction. Vaccinia virus is the prototypical recombinant poxvirus and can generate potent antibody and T-cell responses. This property has led to the use of recombinant vaccinia viruses as a vaccine against HIV and cancer. The isolation of viruses that do not replicate in mammalian cells provides a source of recombinant vectors for when transient gene expression may be required for a longer period of time. The identification of molecular mediators of host immunity, such as cytokines, co-stimulatory molecules and chemokines, provides another method for manipulating innate and adaptive immune responses to recombinant poxvirus vectors and expressed transgenes. This review focuses on the current status of recombinant poxviruses as vectors for gene therapy of human disease.