Clinical management of metastatic melanoma suffered historically from a lack of effective targeted and immunotherapies due to short-lived clinical responses. Recent advances in our understanding of tumor-immune signaling pathways, discovery of immunosuppressive checkpoints, and subsequent development of antibodies that target these checkpoints reverses the situation to some extent. Two antibodies ipilimumab and nivolumab gained Food and Drug administration approval for the treatment of metastatic melanoma and target two major immunosuppressive checkpoints cytotoxic T lymphocyte antigen and programmed cell death protein 1 (PD-1), respectively. Nivolumab binds to PD-1, prevents PD-1 interaction with ligand Programmed death ligand 1 (PD-L1), and thus releases the T-cell exhaustion events (such as T cell apoptosis, decrease in T cell proliferation, etc.) leading to buildup of potent tumor-specific immune response. Successful Phase I-III results with remarkable antitumor activity and safety led to approval of nivolumab against ipilimumab refractory metastatic melanoma. Nivolumab therapy is exciting in that it not only provides substantial benefit but also provides durable responses. This review focuses on the evolution of immunotherapy leading to nivolumab approval and its potential in treating melanoma either alone or in combination with other therapies.