Type 1 (insulin-dependent) diabetes mellitus results from a T cell-mediated autoimmune destruction of the pancreatic β cells in genetically predisposed individuals. Therapies directed against T cells have been demonstrated to halt the disease process and prevent recurrent β-cell destruction after islet transplantation. Less is known about the nature and function of these T cells, the cause of the loss of tolerance to islet autoantigens, why the immune system apparently fails to suppress autoreactivity, and whether (or which) autoantigen(s) are critically involved in the initiation or progression of disease. Autoreactive T cells have proven to be valuable targets to study pathogenic or diabetes-related processes. Measuring T-cell autoreactivity also provided critical information to determine the fate of islet allografts transplanted to type 1 diabetic patients. Furthermore, these studies have provided proof of operational immunologic tolerance to islet allografts as well as valuable information to improve and customize immunosuppressive therapy. Currently, technologies to detect T-cell auto- and alloreactivity in type 1 diabetic recipients of islet allografts are applied to monitor islet allograft survival in relation with various immunosuppressive therapies and to guide tapering of these therapies after successful restoration of insulin production. Although it is generally appreciated that studies on cellular auto- and alloimmunity are hampered by the complex nature of such immune responses and the required technical and physical skills, it has been a worthwhile quest to unravel the role of T cells in the pathogenesis of type 1 diabetes and islet allograft destruction.