Naked plasmid DNA can be used to introduce genetic material into a variety of cell typesin vivo. However, such gene transfer and expression is generally very low compared with that achieved with viral vectors and so is unsuitable for clinical therapeutic application in most cases. This difference in efficiency has been substantially reduced by the introduction ofin vivoelectroporation to enhance plasmid delivery to a wide range of tissues including muscle, skin, liver, lung, artery, kidney, retina, cornea, spinal cord, brain, synovium, and tumors. The precise mechanism ofin vivoelectroporation is uncertain, but appears to involve both electropore formation and an electrophoretic movement of the plasmid DNA. Skeletal muscle is a favored target tissue for three reasons: there is a pressing need to develop effective therapies for muscular dystrophies; skeletal muscle can act as an effective platform for the long-term secretion of therapeutic proteins for systemic distribution; and introduction of DNA vaccines into skeletal muscle promotes strong humoral and cellular immune responses. All of these applications are significantly improved by the application ofin vivoelectroporation. Importantly, the increased efficiency of plasmid delivery following electroporation is seen in larger species as well as rodents, in contrast to the decreasing efficiencies with increasing body size for simple intramuscular injection of naked plasmid DNA. As this electroporation-enhanced non-viral gene delivery system works well in larger species and avoids the vector-specific immune responses associated with recombinant viruses, the prospects for clinical application are promising.