Type 2 diabetes is a major cause of morbidity and mortality worldwide. Identification and characterization of genes affecting susceptibility to type 2 diabetes would substantially impact public health by providing biological and clinical data about development of this trait. Our long-term goals are to identify genes that influence type 2 diabetes susceptibility and to understand their effects on biological processes. A significant challenge in studying genetic susceptibility to any complex trait is validating potential genes. We recognize potential susceptibility genes in humans using large sample sets and high-throughput technologies. Currently, we validate genes using high-resolution mapping in wild-derived and laboratory mouse strains, focused on genes that function through cis-acting regulatory variation. Validated genes will provide insight into the pathways and processes affecting type 2 diabetes susceptibility and will lead to study of genetic interactions with environmental factors.