The development of new treatment options has dramatically improved the landscape for patients with advanced melanoma. Part of these advances emerged through the identification of the importance of factors that regulate the immune system, including proteins that negatively modulate T cell–mediated responses termed “immune checkpoints.” Indeed, blockade of the cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) immune checkpoint served as a proof of principle that the manipulation of these molecules could induce robust anticancer effects, yet limited to a small percentage of patients. Targeting a distinct checkpoint, the PD-1 yielded improved outcomes and reduced toxicity compared with CTLA-4 blockade and, in separate studies, chemotherapy. More recently, combined CTLA-4/PD-1 blockade was shown to result in higher response rates, while accompanied by increased toxicity. In this article, we review the clinical development of anti–PD-1 monotherapy and combinations that may expand the benefit of immunotherapy for patients with advanced melanoma.