This presentation is an overview of mechanisms for developing and maintaining self-tolerance in mammalian organisms. Because this meeting is focused on type 1 diabetes and its mechanisms, the discussion deals primarily with mechanisms of T-cell tolerance, since type 1 diabetes in both effector and initiator phases is primarily a T-cell-mediated autoimmune disease. Emphasis is placed on more recently discovered mechanisms of maintaining self-tolerance (autoimmune regulator [AIRE]) and a new defect in T-cell negative selection. The emerging picture is that of a polygenic disease with various combinations of different alleles of many genes with important roles in the normal immune response or normal immune responses.