The non-obese diabetic (NOD) mouse spontaneously develops autoimmune type I insulin-dependent diabetes mellitus (IDDM) with a similar immunopathological profile to the human disease. Development of the disease in both the NOD mouse and in humans is under polygenic control and influenced by many environmental factors. Diabetes results from a specific T cell-mediated destruction of pancreatic insulin-producing islet beta cells. Both CD4 and CD8 T cells as well as macrophages are required for the development of diabetes in NOD mice. An intriguing similarity between murine and human diabetes is a T cell proliferative unresponsiveness (anergy) that may be a susceptibility factor to disease onset. Defective communication between antigen-presenting cells (APC) and T cells, and/or an aberrant production or activity of inflammatory cytokines (e.g. chemokines) in the thymus and periphery (e.g. pancreas) may account for the unresponsiveness of regulatory T cells leading to a loss of immunological tolerance to beta cell autoantigens in NOD mice and in diabetic humans.