DNA vaccination, or genetic immunization, is a novel vaccine technology that has great potential for reducing infectious disease and cancer-induced morbidity and mortality worldwide. Since their inception, DNA vaccines have been used to stimulate protective immunity against many infectious pathogens, malignancies, and autoimmune disorders in animal models. Plasmid DNA encoding a polypeptide protein antigen is introduced into a host where it enters host cells and serves as an epigenetic template for the high-efficiency translation of its antigen. An immune response, which is mediated by the cellular and/or humoral arms of the immune system and is specific for the plasmid-encoded antigen, ensues. It is thought that “professional” antigen-presenting cells play a dominant role in the induction of immunity by presenting vaccine peptides on MHC class I molecules, following direct transfection or “cross”-presentation, and MHC class II molecules after antigen capture and processing within the endocytic pathway. The correlates of immunity can be manipulated according to many immunization parameters, including the method of vaccine delivery, presence of genetic adjuvants, and vaccine regimen. DNA vaccines first advanced to the clinic five years ago, and the initial picture of their utility in humans is emerging. However, further analysis is required to determine their ultimate efficacy and safety in human beings. This technology has acquired a strong foothold in the field of experimental immunotherapy, and it is hoped that it will eventually represent the next generation of prophylactic and therapeutic vaccines.