Melanoma is one of the most malignant tumors that metastasizes aggressively by lymphatic and hematogenous routes. Because of the resistance of melanoma cells to many types of chemotherapy, the disease causes a high mortality rate. High hopes are pinned on gene therapeutic approaches to melanoma treatment. At present, one of the main problems of the efficient use of postgenomic-generation therapeutic means is the lack of optimal techniques for delivering foreign genetic material to the patient's target cells. Specific surface markers of melanoma cells can be considered as promising therapeutic targets. The review describes currently known melanoma-specific receptors and melanoma stem cells and considers the data on melanoma antigens presented on the cell surface by major histocompatibility complex proteins. The ability of surface proteins to be internalized might be successfully used to develop methods of targeted delivery of therapeutic gene constructs. In conclusion, a concept of multilevel gene therapy and the possible role of surface determinants as targets of gene system delivery to the tumor are discussed. © 2011 Pleiades Publishing, Ltd.