Recent demonstrations of the immunogenicity of antigens encoded in DNA plasmids following delivery by various routes have heralded a new era in vaccine development. In this article, we review progress in DNA-based antiviral immunoprophylaxis. Preclinical studies have already established the immunogenicity of DNA plasmids encoding protective antigens from a wide variety of viral pathogens and work published in recent months has raised real prospects of broadly protective DNA vaccination against infections with influenza virus and HIV. We also describe a consecutive immunization protocol consisting of a priming dose of vaccine antigen encoded in DNA plasmids followed by a booster with the same antigen encoded in recombinant fowlpox virus vectors. We have used this strategy to generate protective antiviral cell-mediated immunity and sustained, high-level antibody responses both systemically and at mucosae, and to elucidate immunological mechanisms underlying the development of immunity to antigens delivered in DNA vectors.