Vaccines represent the most commonly employed immunologic intervention in medicine today. Indeed, they are currently one of the few antigen-specific approaches with clearly documented clinical success. Current estimates by the Centers for Disease Control indicate that greater than 5,000, OOO doses of vaccine against some infectious organism are administered yearly in the United States, making vaccines the most commonly administered immunotherapeutic. Current vaccines target only a tiny fraction of infectious diseases, since prophylaxis against some of the most common and deadly infections in the third world is limited by expense and ease of distribution. In addition to the public health concerns of expense and distribution, other features of current vaccines limit their efficacy. While most current vaccines typically elicit reasonable antibody responses, cellular responses (in particular, major histocompatibility complex [MHC] class l-restricted cytotoxic T cells) are generally absent or weak. For many infectious diseases, such as tuberculosis and malaria, humoral responses have been shown to be of little protective value against infection. Another limitation of most current vaccines relates to the limited duration of immunologic memory. Ideal vaccines would provide lifelong prophylaxis, a goal generally not achieved by current formulations. In the last three years, DNAvaccines have burst onto the scene as a radically new approach to infectious disease prophylaxis. One of the most surprising and important features of DNA immunization is that purified “naked” DNA appears to be taken up and expressed by cells in vivo with much greater efficiency than would have been predicted by the experience with DNA transfection in tissue culture. This finding provides the basis for a critical pharmaceutical advantage of DNAvaccines: namely, simplicity of preparation. In addition, naked DNA can be produced in large scale with tremendous purity, allowing for freedom from contamination with potentially dangerous agents. The final pharmaceutical advantage of DNA is its tremendous stability relative to proteins and other biologic polymers, a feature likely to be more relevant for the production of vaccines than the recreation of dinosaurs. From an immunologic perspective, the unique ability of DNA to either integrate stably into the genome or be maintained long-term in an episomal form provides the potential for long-lived antigen expression. This feature thus has implications for the duration of immunologic memory achievable with nucleic acid vaccines. Despite the flurry of reports documenting the ability of naked DNA vaccines to induce both immunologic and protective responses in animal models, the mechanism by which DNA injections activate the immune system against the encoded antigens