The immune checkpoint inhibitors ipilimumab, nivolumab, and pembrolizumab have dramatically improved outcomes for patients with metastatic melanoma; however, not all patients benefi t from monotherapy with these agents. To address this issue, complementary combinations of immunotherapy are increasingly being explored as a strategy to improve outcomes. However, combinatorial approaches come with heightened risk of toxicity. In this review, we highlight combinations for which there are prospective data from clinical trials. The combinations discussed include ipilimumab plus anti--programmed death 1 agents, ipilimumab plus granulocyte-macrophage colony-stimulating factor, checkpoint inhibitor plus talimogene laherparepvec, ipilimumab plus chemotherapy, checkpoint inhibitor plus BRAF/MEK targeted therapy, and checkpoint inhibition plus radiation therapy. We discuss data regarding the effi cacy and toxicity of combination therapy, and we identify clinical scenarios that may favor treatment with combination therapy.