Preclinical in vivo rodent, porcine, and primate experiments aimed at enhancing nonviral transgene delivery to skin have been performed. These investigations have identified a compound (aurintricarboxylic acid or ATA) that enhances transfection activity of "naked" plasmid and pulsed electrical fields (electroporation or EP) that synergistically boosts transgene expression to an average of 115-fold more than that observed with free DNA (P < 0.00009). When plasmid is intradermally injected with or without ATA, the transfected cells are typically restricted to the epidermis. However, when electroporation is added after the same injection, larger numbers of adipocytes and fibroblasts and numerous dendritic-like cells within the dermis and subdermal tissues are transfected. This advance creates new opportunities for cutaneous gene therapy and nucleic acid vaccine development.