Genes influence susceptibility to type 2 diabetes mellitus (T2DM), and both positional cloning and candidate gene approaches have been used to identify these genes. Linkage analysis has generated evidence for T2DM-predisposing variants on chromosome 20q in studies of Caucasians, Asians, and Africans, and fine-mapping recently identified a likely susceptibility gene, hepatocyte nuclear factor 4-alpha (HNF4A). Rare loss-of-function mutations in HNF4A cause maturity-onset diabetes of the young and now common noncoding variants have been found to be associated with T2DM.