Non-viral delivery of cell-impermeant drugs and DNA in vivo has traditionally relied upon either chemical or physical stress applied directly to target tissues. Physical methods typically use contact between an applicator, or electrode, and the target tissue and may involve patient comfort. To overcome contact-dependent limitations of such delivery methodologies; and atmospheric helium plasma source was developed to deposit plasma products onto localized treatment sites. Experiments performed in murine skin showed that samples injected with plasmid DNA encoding luciferase and treated with plasma demonstrated-increased levels of expression relative to skin samples that received injections of DNA alone. Increase response relative to injection alone was observed when either positive or negative voltage was used to generate the helium plasma. Quantiative results over a 26-day follow-up period showed that luciferase levels as high as 19-fold greater than the levels obtained by DNA injection alone could be achieved. These findings indicate that plasmas may complete with other physical delivery methodologies when skin is the target tissue. Biotechnol. Bioeng. 2009;104: 1034-1040. (C) 2009 Wiley Periodicals, Inc.