Immune augmentation with ipilimumab, an anti-CTLA-4 monoclonal antibody, has joined the ranks of approved immunologic agents for the treatment of metastatic melanoma. Phase III studies of ipilimumab in metastatic melanoma have demonstrated an overall survival advantage as compared to other approved and investigational therapies. However, the adverse effects associated with this medication are unique and often require management with steroids or other immunosuppressants. In addition, the time to response differs with ipilimumab as compared to traditional chemotherapy, and alternative means of assessment of response have been proposed. In this review, we will summarize the basic science of this treatment, its preclinical evaluation, and the clinical trials leading to its approval. We will also discuss the details regarding its use, assessment of response to this drug and other immune-related therapies, and further directions for investigation.