Survival of melanoma varies widely by stage, from a potentially highly curable disease when detected in early stages, to a disease with dismal prognosis when it reaches advanced inoperable stages. Stage IV melanoma defines distant metastasis and continues to comprise an ominous prognosis, with a median survival of 6-9 months. Currently, there is no therapeutic agent known to prolong survival in patients with metastatic melanoma. Therapeutic approaches studied in metastatic melanoma include chemotherapy, biochemotherapy, nonspecific immune adjuvants, cancer-specific vaccines, cytokines, monoclonal antibodies, and specific immunostimulants. Chemotherapy with single-agent dacarbazine is the only United States Food and Drug Administration (US-FDA)-approved chemotherapy agent for metastatic melanoma. Immunological approaches have yielded the only newly US-FDA-approved agent for metastatic disease in 30 years, high-dose bolus IL-2, based on durable responses in some patients with metastatic melanoma, but with associated high toxicity rate and cost. A number of novel therapeutic agents are undergoing active clinical investigation.