Establishing a balance between the rapid generation of effective immunity and the production of overly exuberant or excessively prolonged responses is critical to the maintenance of the equilibrium between health and disease. The preservation of homeostasis and prevention of inappropriate activation of immunity is safeguarded by systems integrating the influences of T‐cell receptor signaling, pro‐inflammatory danger signals, and positive costimulatory signals on the one hand with those of several layers of both cell‐intrinsic and cell‐extrinsic inhibitory checkpoints on the other. Evolution has thus provided an immunological system capable of clearance of pathogens and infected cells but which generally avoids the severe collateral damage that is associated with failure to control immunity. Central tolerance to self‐antigens constitutes the first line of defense against self‐destruction. Because central tolerance mechanisms fail to eliminate all self‐reactive immune effector cells, other immune‐regulating (peripheral tolerance) mechanisms are required to prevent excessive immune responses. Dysfunction of these inhibitory pathways in terms of reduced activity can result in the unmasking of self‐directed responses and a variety of autoimmune morbidities. Conversely, enhanced inhibitory activity can restrict the generation of clinically useful immunity to cancers and to chronic infectious pathogens. This may manifest not only as inhibition of immunity directed towards what are largely aberrantly or overexpressed ‘self’ targets on malignant cells but also additional exaggeration of inhibitory pathway activity mediated via upregulation on tumor cells or stromal tissues of the ligands for inhibitory receptors expressed by lymphocytes. The selective pressures exerted by immuno‐editing will favor the outgrowth of such immuno‐evasive malignant clones. These pathways therefore represent significant hurdles to the generation of therapeutic anti‐cancer responses. The most active of the T‐cell intrinsic inhibitory pathways belong to the immunoglobulin superfamily, which occupies a central importance in the coordination of immune responses. The CD28/cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4):B7‐1/B7‐2 receptor/ligand grouping represents the archetypal example of these immune regulators. Therapies aimed at overcoming these mechanisms of peripheral tolerance, in particular by blocking the inhibitory checkpoints, offer the potential to generate anti‐tumor activity, either as monotherapies or in synergism with other therapies that directly or indirectly enhance presentation of tumor epitopes to the immune system.