SAP (SLAM-associated protein) was identified in 1998 as an adaptor molecule involved in the intracellular signaling pathways elicited through the cell surface receptor SLAM and as the protein defective in the human immunodeficiency X-linked lymphoproliferative disease (XLP). During the past eight years, it has been established that the SLAM family of cell surface receptors (SLAM, 2B4, NTB-A, Ly9, CD84) and the SAP family of adaptors (SAP, EAT-2, ERT) play critical roles in lymphocyte development, differentiation, and acquisition of effector functions. Studies of these proteins have shown unexpected roles in cytokine production by T cells and myeloid cells, T cell–dependent humoral immune responses, NK cell–mediated cytotoxicity, and NKT cell development. This review highlights recent findings that have improved our understanding of the roles of the SLAM and SAP families of molecules in immune regulation and discusses how perturbations in the signaling pathways involving these proteins can result in different disease states.