BACKGROUND The recent developments in the field of gene transfer have advanced the use of gene therapy as a novel strategy against a variety of human malignancies. Due to its unique set of characteristics, melanoma represents a suitable target for the clinical translation of the different gene transfer approaches recently developed. The goal of gene therapy targeted to melanoma cells is to introduce "suicide" genes, to transfer tumor suppressor genes, to inactivate aberrant oncogene expression, or to introduce genes encoding immunologically relevant molecules. Gene therapy targeted to the host's immune cells has been developed as an additional strategy to redirect immune responses against melanoma. METHODS The authors reviewed the published gene transfer studies in experimental models, as well as the results of gene therapy clinical trials for patients with melanoma. RESULTS Clinical trials have shown the feasibility and safety of gene therapy against malignant melanoma. Although no major successes have been reported, the positive results observed in some patients support the potential for gene therapy in the management of this disease. CONCLUSIONS Gene therapy of melanoma using current gene transfer approaches is feasible and safe. Better vector technology as well as increased understanding of the "bystander effect" triggered by gene transfer approaches would provide the tools to validate gene therapy as an effective modality of treatment for malignant melanoma.