The signaling lymphocyte activation molecule (SLAM) family of receptors and their associated signaling adaptors play a pivotal role in the regulation of various stages of cellular immunity. They regulate lymphocyte-lymphocyte interactions involved in both cell-mediated and humoral immune responses. Recent evidence indicates that members of this family of receptors and signaling intermediates are also involved in autoimmunity. These include strictly correlative studies showing increased expression of various family members in immune effectors involved in rheumatoid arthritis and in inflammatory bowel disease, as well as more direct evidence (from various knockout strains of mice) for their role in autoimmune processes such as experimental allergic encephalomyelitis and lupus. Additional studies defining naturally occurring polymorphic variations in the SLAM family show a direct role in initiating the break in tolerance that is an essential step in the progression towards autoimmunity.