The incidence of cutaneous melanoma has been rapidly increasing, with an estimate of 47,700 new cases diagnosed in 2000 in the United States. In the early phase of its natural history, melanoma is cured in most cases by surgery, but once the metastatic phase develops, it is almost always fatal. The treatment of metastatic melanoma remains unsatisfactory. Systemic therapy has not been successful up to now, with very low response rates to single-agent chemotherapy. Polychemotherapy has increased the response rate (RR), without a significant improvement in overall survival. Immunotherapy alone is able to induce only a few durable complete responses (CRs). New chemotherapeutic and biologic agents are now available and promising combined approaches targeting the tumor by several different mechanisms are desirable and will probably represent the future modality of treatment.