Melanoma is a neoplasm with a rising incidence. Early-stage melanoma is curable, but advanced, metastatic melanoma almost uniformly is fatal, and patients with such advanced disease have a short median survival. Systemic therapy remains unsatisfactory, inducing complete durable responses in a small minority of patients. For the current review, the authors focused on the current role of cytotoxic chemotherapy in the treatment of metastatic melanoma and the future prospects for improvements for multiagent chemotherapy and chemotherapy combined with immunomodulatory and/or molecularly targeted agents. They discuss roles of single-agent chemotherapy, combination chemotherapy, combinations of chemotherapy with immunomodulatory or hormone agents, biochemotherapy, and combination chemotherapy with targeted therapies. Cancer 2007;109:455–464. © 2007 American Cancer Society.