Similar to the vast majority of cases in humans, the development of type 1 diabetes (T1D) in the NOD mouse model is due to T-cell mediated autoimmune destruction of insulin-producing pancreatic β cells. Particular major histocompatibility complex (MHC) haplotypes (designated HLA in humans and H2 in mice) provide the primary genetic risk factor for T1D development. It has long been appreciated that within the MHC, particular unusual class II genes contribute to the development of T1D in both humans and NOD mice by allowing for the development and functional activation of β-cell autoreactive CD4 T cells. However, studies in NOD mice have revealed that through interactions with other background susceptibility genes, the quite common class I variants (K d, D b) characterizing this strain's H2 g7 MHC haplotype aberrantly acquire an ability to support the development of β cell autoreactive CD8 T-cell responses also essential to T1D development. Similarly, recent studies indicate that in the proper genetic context some quite common HLA class I variants also aberrantly contribute to T1D development in humans. This chapter will focus on how "humanized" HLA transgenic NOD mice can be created and used to identify class I-dependent β cell autoreactive CD8 T-cell populations of clinical relevance to T1D development. There is also discussion on how HLA transgenic NOD mice can be used to develop protocols that may ultimately be useful for the prevention of T1D in humans by attenuating autoreactive CD8 T-cell responses against pancreatic β cells.