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Targeted therapy and checkpoint inhibitors have been approved by US Food and Drug Administration (FDA) and European Medical Agency (EMA) for advanced and adjuvant treatment of melanoma. The first checkpoint inhibitor to be approved by FDA and EMA for treatment of melanoma was ipilimumab, a human cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody, based on proven benefit in terms of overall survival and recurrence-free survival in advanced and early disease, respectively. Programmed death-1 (PD-1) checkpoint inhibitor nivolumab was approved in advanced disease in 2014 and for the adjuvant treatment of stage IIIB–IIIC/stage IV melanoma in 2017 on the basis of an improvement in recurrence-free survival versus the active comparator ipilimumab. In this chapter, we review the activity, efficacy, and toxicity of nivolumab and summarize new potential therapeutic strategies, which could potentially expand its spectrum of activity in melanoma.