Clinical and laboratory observations suggest that host immunological responses may occasionally influence the course of melanoma, stimulating the investigation of immunotherapy approaches in this disease. Areas of active investigation have included recombinant cytokines, either alone or in combination with chemotherapeutic regimens or other biological response modifiers, such as vaccines, monoclonal antibodies, dendritic cells and gene therapy. To date, the benefit of these approaches in patients at high-risk of recurrence or advanced disease has been modest. Although many of these novel strategies are limited by weak antigen presentation, tumor-induced tolerance and tumor heterogeneity, it is possible that these approaches will prove more useful when given in combination.