For several decades, the central hypothesis underlying type 1 diabetes pathogenesis has been that autoreactive T lymphocytes kill the only cells in the body that can make insulin, i.e. the so called beta cells in the pancreatic islets of Langerhans. Considerable data supports that hypothesis, and yet no therapies have been developed with sufficient safety and efficacy to be used clinically.  It is fair to ask if gaps in our understanding of disease mechanisms may be at play and several large knowledge gaps can be identified.  The lecture will review the data supporting the central hypothesis of T1D pathogenesis, but then also some of the major questions that remain to be answered.