Studies in the field of T-cell receptor (TCR)/antigen (Ag) recognition have led to the discovery of a unique receptor/ligand system that, in collaboration with TCR/Ag engagement, underlies the molecular basis of T-cell activation and proliferation. Such a process has been termed co-stimulation, which serves to either upregulate or downregulate T-cell signaling following TCR ligation. As neoplasia represents a pathogenic process whereby a sustained T-cell response may be desirable, intensive efforts to prolong endogenous tumor-induced T-cell activity in vivo have been investigated. One innovative approach has been to block a crucial inhibitory arm of the co-stimulatory pathway using monoclonal antibodies against the CTLA-4 molecule expressed by Ag-primed, activated T-cells. In both preclinical models and clinical settings, such a therapeutic intervention has been found to be effective in promoting antitumor T-cell responses and, in some patients, clinical regression has been concomitant with autoreactivity. Thus, CTLA-4 blockade, perhaps in conjunction with other oncological modalities, may comprise important therapeutic paradigms to facilitate long-lasting antineoplastic immunity.