Despite the expression of antigens by tumor cells, spontaneous immune-mediated rejection of cancer seems to be a rare event. T-cell receptor engagement by peptide/major histocompatibility complexes constitutes the main signal for the activation of naive T cells but is not sufficient to initiate a productive generation and maintenance of effector cells. Full activation of T cells requires additional signals driven by costimulatory molecules present on activated antigen-presenting cells but rarely on tumors. Following the discovery of B7-1 (CD80), several other costimulatory molecules have been shown to contribute to T-cell activation and have relevance for improving anti-tumor immunity. Moreover, increasing the understanding of coinhibitory receptors has highlighted key additional pathways that can dominantly inhibit anti-tumor T-cell function. Improving positive costimulation, and interfering with negative regulation, continues to represent an attractive immunotherapeutic approach for the treatment of cancer. This review focuses upon those pathways with the highest potential for clinical application in human cancer patients.