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Antigens encoded by DNA vaccines can induce all arms of the adaptive immune response, but to date they have proven most effective at inducing antigen-specific CD8+ T cells. The great majority of experiments have been carried out in small animal models, where these vac- cines work quite well; in a limited number of studies in primates (including humans), their effectiveness, although demonstrable, is somewhat diminished. Therefore, to accelerate the introduction of DNA vaccines into clinical and veterinary practice, it is important that their immunogenicity be enhanced. The rational modification of DNA vaccines requires that we have a basic understanding of the mechanisms which underpin successful DNA immuniza- tion. In this chapter, we review how DNA vaccines may work, and how this information per- mits us to exploit biological pathways to improve the outcome of genetic immunization. In addition to reviewing "rational" vaccine modification (based on, e. g. , targeting antigens to specific antigen presentation pathways; or co-administering cytokines to modulate the vaccine-induced response) we also consider "empirical" approaches, such as using different prime-boost regimens which-by a mechanism as yet unclear-appear to greatly enhance antigen-specific memory in the vaccinee. Empirical studies proved the efficacy of essentially all vaccines in current use, and this old approach may once again prove useful in launching a new technology into the clinical arena. References 1. Whitton JL. Lymphocytic choriomeningitis virus CTL. Sem Virol 1990; 1:257-262. 2. Good RA. and Zak SJ. Disturbance in gamma-globulin synthesis as "experiments of nature".