Melanoma is an aggressive disease with few effective treatment options. Non-toxic, anti-tumor therapies and prophylactic approaches are currently being investigated to identify treatment options that will control and remove late-stage melanoma. The overall goal of this project was to establish an effective delivery method for a plasmid encoding human interleukin (phIL-15) into mouse melanoma cells (B16.F10) using the gene transfer technique electroporation (EP)1. The EP delivery phIL-15 was optimized using an in vitro 3D tumor model. The purpose was to translate these IL-15 delivery conditions into an in vivo mouse melanoma model to study IL-15 signal transduction and stimulate immune cells to destroy tumor antigens as well as promote an anti-tumor immune memory response. The in vitro 3D tumor model and the mouse model demonstrated similar expression patterns when delivering phIL-15 with different EP conditions. Intra-tumoral delivery using 500V/cm 20ms enhanced gene delivery and increased IL-15 protein expression compared to 1300V/cm 100μs. There was also a visible increase in transfection efficacy between tumor cells compared to skin cells when delivering pmIL-12 and phIL-15 plasmid constructs in vivo. The plasmid+EP groups 1300V/cm and 500V/cm stimulated increased expression of cytokines IL-1β, IL-6, INFγ, MIP-1β and TNFα. These EP groups also promoted tumor regression by up-regulating CD8+ T cells and CD4+ T cells which targeted melanoma. Regression and survival studies demonstrated that 73.3% of mice cleared B16.F10 cells when treated with phIL-xi15+1300V/cm and pVax+500V/cm. In addition, 53% of the mice responded to the phIL-15+500V/cm treatment group. Furthermore, 75% of the mice from group phIL-15+500V/cm survived secondary inoculation and tumor challenge. In conclusion, plasmid with encoding gene insert phIL-15 delivered by EP has the potential to act as an anti-tumor therapy because it promotes melanoma regression and enhances mouse survival through innate and adaptive cell-mediated immune responses.