The ability of activating immune recognition receptors on lymphocytes to regulate cellular activation and function can be profoundly altered by co-stimulation with inhibitory receptors. Inhibitory receptors, such as the MHC-recognizing inhibitory receptors expressed on NK cells and subpopulations of activated T cells, can fully block the generation of any cytotoxic function by targeting proximal signals. Inhibitory Fc receptors on B cells, macrophages and mast cells can influence their threshold for activation, but the induction of inhibitory Fc receptors also appears to play a major role in the attenuation of ongoing responses. The three identified groups of inhibitory B7-recognizing receptors (CTLA-4, PD-1 and BTLA) are only expressed on activated hematopoietic cells, thus exclusively regulating ongoing immune responses in lymphoid organs and the periphery. In each case, the integrated positive and negative regulatory events determine the nature of the functional response.