Little more than 10 years ago, metastatic melanoma was considered to have one of the poorest cancer outcomes, associated with a median overall survival of 6-8 months. Cytotoxic chemotherapy offered modest response rates of 20%-30%, but no clear survival benefit. Patients were routinely enrolled in clinical trials as their first-line therapy in the search for effective novel therapeutics. Remarkable developments in molecular biology, cancer genomics, immunology, and drug discovery have dominated the early part of the 21st century, and nowhere have the benefits been better realized than in the transformation of outcomes for patients with metastatic melanoma: since 2011, 14 new agents have been approved that significantly increase survival, with long-term remissions and, possibly now, potential for cure. Even so, there is still much work to be done, given that most treated patients still die of their disease. Although most survival gains have so far been realized for cutaneous melanoma, improving treatment options for those 10% of patients with rarer, noncutaneous melanomas is a high priority. Key novel therapeutic approaches aimed at improving outcomes with potential for curing patients with melanoma are considered.