The cytotoxic T lymphocyte-associated protein 4 (CTLA4) is a main negative regulator of the immune system, which inhibits the costimulatory signaling for T cells. Preclinical studies demonstrated that antibodies against CTLA4 induced regression of some murine tumors. Two CTLA4 blocking monoclonal antibodies have entered clinical development and are currently in pivotal clinical trial testing. Ipilimumab (formerly MDX010) is an IgG1 and tremelimumab (formerly CP-675,206 and transiently ticilimumab), is an IgG2, both being fully human monoclonal antibodies. Across several early clinical trials, including dose escalation, single dose, multi-dose, and in combination with a variety of other immune stimulants like peptide vaccines or interleukin-2, objective tumor responses in patients with metastatic melanoma have been observed in the in the range of 5 to 20%. A key feature is that some of these responses are extremely long-lived responses, lasting years. The early clinical testing also demonstrated that these CTLA4 blocking antibodies can lead to significant toxicities, most with an inflammatory or immune mediated mechanism of action. These include colitis and skin rash as the most common toxicities, and a variety of autoimmune and inflammatory processes against multiple organs. Some of these toxicities require immune suppressive therapy and may lead to permanent damage in occasional patients. In conclusion, two monoclonal antibodies blocking CTLA4 have demonstrated ability to break tolerance to self-tissues and result in long lasting objective cancer regressions, and have moved onto late stages of clinical development.