Evaluation of: Hodi FS, O'Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363(8), 711-723 (2010). Interference with the inhibitory immune regulatory checkpoints that act to constrain overly exuberant immune responses and help to maintain peripheral tolerance represents an exciting new paradigm in tumor immunotherapy. We review the study of Hodi and colleagues evaluating the role of blockade of one of these pathways (cytotoxic T-lymphocyte antigen-4) with a monoclonal antibody (ipilimumab, developed by Medarex, NJ, USA and Bristol-Myers Squibb, NY, USA) in patients with advanced melanoma who had failed prior treatments. The randomized Phase III study demonstrates superior overall survival in patients receiving ipilimumab, either alone or in combination with a gp100 peptide vaccine, compared with those receiving the vaccine alone. The results represent the first positive randomized clinical trial ever reported in patients with metastatic melanoma in terms of overall survival, the first showing a beneficial effect of a melanoma treatment in the second-line setting, and the first demonstration that blockade of an immune-inhibitory pathway can be an effective cancer therapeutic.