Cancer immunotherapy utilizing vaccines has relied upon the patients' pre-existing immune activation capabilities, augmented by existing adjuvants, to promote tumor-antigen specific immune responses. Generating effective antitumor responses in this way requires overcoming multiple mechanisms of tumor evasion of the immune system. In addition, the generation of tumor immunity must overcome tolerance to tumor antigens, which in most cases are self-antigens. One approach to generate more effective immune responses to tumors is through the manipulation of co-stimulatory molecules that control T-cell reactivity through both positive and negative signaling mechanisms. This review will focus on the T-cell co-stimulatory molecule CTLA4. Engagement of CTLA4 by the ligands B7-1 and B7-2 imparts a negative signal to T-cells and results in alteration of T-cell activity and selection. In murine tumor models, antibodies to CTLA4 can promote tumor rejection and tumor immunity. Antibodies to human CTLA4 have entered clinical trials and demonstrated objective clinical responses, initially for metastatic melanoma. Interestingly, CTLA4 blockade has been associated with organ-specific inflammatory adverse events. These events usually respond readily to short-term anti-inflammatory treatment and cessation of drug treatment, and even when suppressed in this manner appear to correlate with clinically significant and durable antitumor responses.