Insulin is a polypeptide hormone secreted by pancreatic β-cells and is critical for glucose homeostasis. Abnormalities in insulin secretion result in various forms of diabetes. Type 1A diabetes is an autoimmune form in which insulin has been identified as a critical autoantigen. Recent studies have identified genetic determinants of insulin-specific autoimmune responses and insulin epitopes targeted by autoreactive T lymphocytes. The study of insulin as an autoantigen has also led to discoveries about basic mechanisms of immunological tolerance and autoimmunity. Experimental and clinical evidence suggests that insulin and insulin-derived peptides may delay and perhaps prevent the development of diabetes. Further clinical trials may identify effective treatment modalities for inhibiting diabetogenic autoimmunity and preventing disease development.