Natural killer cell functions are regulated by a delicate balance between activating and inhibitory signals transmitted by distinct classes of cell surface receptors. 2B4 (CD244), a member of the signaling lymphocyte activation molecule (SLAM/CD150), is expressed on all NK cells, a subpopulation of T cells, monocytes and basophils. Unlike other activating and inhibitory receptors, 2B4 (CD244) interaction with its ligand CD48 has been shown to mediate both activating and inhibitory functions. In human NK cells 2B4 predominantly function as an activating receptor. The activating function of 2B4 requires SLAM- associated protein (SAP). In the absence of SAP in human NK cells, 2B4 acts as an inhibitory receptor. In contrast, studies using 2B4-deficient mice suggest that the major function of mouse 2B4 is to inhibit murine NK cell function. This inhibitory function of murine 2B4 is mediated by EAT-2, ERT and possibly other phosphatases like SHP-1 and SHP-2. 2B4-mediated stimulation of human NK cell cytolytic function and cytokine production involves distinct signaling pathways. Engagement of surface 2B4 on human NK cells by anti-2B4 antibody or CD48 down-regulates the 2B4 gene transcription as well as surface expression of 2B4. The modulation of expression of surface 2B4 may therefore be a mechanism for controlling NK cell activation during immune responses.