Systemic chemotherapy for the treatment of metastatic melanoma remains disappointing. Nor new single agent has demonstrated promising results. The combination of cisplatin, decarbazine, carmustine, and tamoxifen appears to be one of the most active regimens with an overall response rate approaching 50%. In some patients, responses have been durable and exceed 3 years. Sequential small phase II trials suggest that tamoxifen is an important component in this combination. The efficacy of the combination of hormonal and chemotherapy, however, needs to be corroborated in a large multicenter phase II trial. In addition, further laboratory and clinical studies are needed to evaluate the role of tamoxifen. Biological response modifiers, such as interleukin-2 and alpha-interferon, have limited activity as single agents, but in combination with cytotoxic agents show some promise and merit further evaluation. Future research should focus on the development of more effective agents, and on the use of aggressive adjuvant and neoadjuvant chemotherapy in high-risk patients with locally advanced disease.