The 10-year survival rate for patients with metastatic melanoma has historically been less than 10%. However, recent successes with immunotherapy and BRAF-targeted therapy have ushered in a new era in systemic therapy of this disease. These therapies have been associated with significant improvements in patient outcomes in several randomized phase III trials. Not only have these breakthroughs increased the likelihood of long-term survival in patients with melanoma, but they have also spurred the investigation of a new generation of agents for treatment of melanoma. This article reviews both current options for systemic treatment of metastatic melanoma and promising investigational approaches. We also discuss important considerations in choosing among systemic therapy options, to match the unique goals of therapy for individual patients.