New medications and combination treatment strategies for patients with metastatic melanoma are discussed.Bcl-2 is an inhibitor of apoptosis that is overexpressed in approximately 80% of melanoma cell lines and is believed to contribute to the development of resistance to cytotoxic chemotherapy in patients with melanoma. Oblimersen, an antisense oligonucleotide that stops the translation of Bcl-2 mRNA to protein, significantly improved progression-free survival when administered in combination with dacarbazine. Overall survival was significantly improved in patients with low levels of serum lactate dehydrogenase (LDH), but not in patients with elevated LDH. RAF proteins are a family of serine/threonine kinases that regulate many aspects of cellular function. RAF mutations occur in 70% of melanoma cell lines. Although RAF kinases are thought to be important in the pathogenesis of melanoma, RAF inhibition with sorafenib has not significantly improved survival in patients with advanced disease. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a naturally occurring inhibitor of T-cell function that prevents the complete activation of T cells upon exposure to antigens by antigen-presenting cells. Two monoclonal antibodies to CTLA-4 (tremelimumab and ipilimumab) have been developed to promote T-cell activation in melanoma and other types of cancer. Phase I and phase II clinical trials of these agents in patients with metastatic melanoma have demonstrated promising effects on tumor progression, with objective response rates of approximately 20% and sustained responses in some patients. Several vaccines have been developed to stimulate immune system responses against melanoma. Despite promising early findings with polyvalent melanoma vaccine and with vaccine containing heat shock proteins, results with these agents in larger clinical trials have been disappointing.Ongoing clinical trials continue to evaluate these and other novel approaches to the treatment of metastatic melanoma.