Studies described in the recent literature support the idea that gene therapy can lead to genuine clinical benefits when mediated by plasmid delivery in conjunction with electroporation. Plasmid-mediated muscle-targeted gene transfer offers the potential of a cost-effective pharmaceutical-grade therapy delivered by simple intramuscular injection. This approach is particularly appropriate for modulating muscle and fat mass and their intrinsic properties, from treatment of conditions such as cachexia associated with chronic diseases, autoimmune diseases, e.g., myasthenia gravis, to stimulation or suppression of appetite, and further to in vivo manipulation of glucose metabolism and fat deposition in patients with diabetes, or to basic studies of muscle-specific transcription factors and their impact in development. Recent innovations, including in situ electroporation, enabling sustained systemic protein delivery within the therapeutic range, are reviewed. Translation of these advances to human clinical trials will enable muscle- and fat-targeted gene therapy to become a viable therapeutic alternative.