The expectation has been that plasmid DNA vaccines may have use against a wide range of microbial and oncologic targets. However, attempts at their development have been hampered by the inability to achieve high, consistent levels of immunogenicity in large experimental species and humans. Successful development is probably contingent on a delivery method that provides robust, consistent antigen expression and immune responses. Electroporation (EP), a promising approach that dramatically enhances expression of the encoded antigen as well as the potency and immunogenicity of DNA vaccines, could facilitate clinical implementation of DNA vaccination. With the recent development of EP systems that enable safe, tolerable, reproducible and clinically acceptable administration, EP-based DNA vaccination has become a clinical reality. The technology is now being tested for safety and immunogenicity in several Phase I clinical trials.