Ipilimumab is a fully human monoclonal antibody directed against the cytotoxic T-lymphocyte antigen-4 receptor. Blocking cytotoxic T-lymphocyte antigen-4 signaling has been shown to enhance T-cell activation and to amplify T-cell-mediated immunity. Ipilimumab, either as a single agent or in combination with gp100 vaccination, significantly prolonged overall survival in a randomized Phase III trial in patients with disease progression after prior treatment when compared with gp100 alone. In previously untreated patients, the addition of ipilimumab to dacarbazine also significantly prolonged overall survival. The most common adverse events are immune related. Adherence to established treatment algorithms in patients with immune-related adverse events is advocated. Predictive factors for the activity of ipilimumab have not been identified but would be of great value in the selection of patients who are most likely to benefit from this innovative immunotherapy. Outstanding issues include the role of ipilimumab in the adjuvant treatment of patients who are at high risk for relapse, and the optimal treatment sequence for patients with BRAFV600 mutant melanoma, as small-molecule BRAF inhibitors have also been shown to improve the survival for this subgroup of patients.