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The successful management of advanced melanoma remains an unmet need because of a resolutely poor prognosis and therapeutic options with limited effectiveness. Dacarbazine and fotemustine are the only approved chemotherapeutic agents for advanced melanoma, yet neither alone or in combination regimens has been shown to extend survival in randomized clinical trials. The only agent to be approved for advanced melanoma in the US in more than 30 years is high-dose bolus interleukin-2, but its use is associated with high toxicity and cost, and it has also failed to show a survival benefit. Our expanding knowledge of the complex factors and pathways regulating immune function has led to the advent of novel immunotherapeutic agents. Among these are ipilimumab and tremelimumab – fully human, monoclonal antibodies directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4). The pivotal role of CTLA-4 in regulating T-cell function is established, and a series of preclinical studies provided proof-of-concept evidence of the antitumor activity of anti-CLTA-4 antibodies in combination with vaccines or chemotherapy. Subsequently, anti-CTLA-4 antibodies have shown encouraging results in clinical trials in advanced melanoma. Recent progress in the understanding of melanoma genetics and tumorigenesis has led to potential new therapeutic targets. Molecular targeted agents that inhibit the proliferation and survival of metastatic melanoma cells offer potential partners for anti-CTLA-4 antibodies in combined modality regimens. Novel combinations are reviewed in the context of creating an immunosupportive environment in the host.