The nonobese diabetic mouse spontaneously develops an autoimmune, T-cell-mediated type 1 diabetes (T1D). Common and rare alleles both within a diabetogenic major histocompatibility complex (MHC) and multiple non-MHC genes combine to impair normal communication between the innate and acquired immune system, leading to loss of immune tolerance. An understanding of how variable collections of genes interact with each other and with environmental cues offers important insights as to the complexities of T1D inheritance in humans.