The nonobese diabetic (NOD) mouse model of insulin-dependent diabetes mellitus (IDDM) has provided evidence which suggests that an important mechanism of the induction of this T-cell-mediated autoimmune disease is a failure in immune regulation. The role of T-cell immune dysregulation in the initiation of diabetes is the focus of this review. Immunological mechanisms such as T-cell anergy and deficient T-cell-mediated suppression are discussed as mediators of IDDM susceptibility. In particular, T helper (Th) 2 cell anergy may be responsible for defective regulation of autoreactive effector T-cells. Therapies designed to overcome these T-cell-mediated deficiencies may prevent IDDM onset.