Purpose of Review: This article provides an update on the therapeutic role of the monoclonal antibody ipilimumab in melanoma. Recent therapeutic combinations, as well as directions for further investigations, will also be discussed. Recent Findings: By blocking the interaction between CTLA-4 and B7 expressed on activated T lymphocytes and antigen-presenting cells, respectively, ipilimumab inhibits negative signals that physiologically downregulate T-cell activation and exerts its therapeutic activity by upregulating the antitumor activity of T lymphocytes. Ipilimumab has been the first agent to significantly improve the survival of metastatic melanoma patients and to provide long-term benefit to a sizeable proportion of patients treated within phase II/III studies and expanded access programs. On these premises, a number of studies combining ipilimumab with cytotoxic, antiangiogenic, and targeted agents have been most recently conducted. Summary: Ipilimumab is the prototype of a growing family of 'immunomodulating antibodies' and it has demonstrated that immunotherapy will play an increasingly important role in the new treatment approaches for cancer. Combinations of chemotherapy, radiation therapy, and targeted drugs with ipilimumab indicate that additive and synergistic antitumor activity can be achieved. Most importantly, they indicate that involving the immune system is a key strategy to improve the outcome in cancer patients.