Type 1 diabetes is an organ-specific autoimmune disease characterized by T cell-mediated destruction of the insulin-producing beta cells of the pancreatic islets. While insulin therapy allows for continuation of life, it neither cures the disease nor prevents its devastating complications. Studies utilizing the nonobese diabetic (NOD) mouse model of the disease have shown that T cells, recognizing autoantigenic peptides bound to major histocompatibility complex (MHC) molecules, are absolutely required for disease development. T cells specific for beta cell antigens can also be detected in the peripheral blood and islets of type 1 diabetes patients. Our laboratory utilizes a combination of in vitro and in vivo models and structural biology approaches to investigate the antigenic specificities, pathogenicity, and immunobiology of T cells in type 1 diabetes. Increasingly humanized models are continually in development in our group, and these are being used to develop and optimize antigen-specific therapeutic strategies. The goals of our work are to better understand the underlying immunopathogenesis of type 1 diabetes and to develop improved tools to monitor and manipulate pathogenic beta cell-specific T cells.