Type 2 diabetes mellitus (DM) is a common metabolic-endocrine disorder often associated with overweight or obesity. It is a complex disease determined by both predisposing genetic factors and non-genetic environmental factors and interactions between them, leading to impaired beta-cell insulin secretion and peripheral insulin resistance. Insulin resistance is a prominent feature of most patients with type 2 DM and obesity, resulting in a reduced response of target tissues (muscle, liver and fat) to both endogenous and exogenous insulin. There is considerable evidence that heredity is a major contributor to the insulin resistance of type 2 DM. Initially, among those destined to develop diabetes, the beta cells of the pancreas compensate with increased insulin secretion to maintain normal glucose tolerance. Type 2 DM develops when beta cells fail to compensate. Despite of the numerous studies in the recent years, the actual genetic causes of insulin resistance and type 2 DM have not yet been clearly elucidated. Through linkage and "genome-wide" studies, genes were identified most frequently associated with type 2 DM, such as TCF7L2, considered, until recently, the most important gene among those predisposing to type 2 DM. On the other hand, numerous candidate genes have been analyzed for genetic variants that increase susceptibility to type 2 DM. Several variants have been identified in many of these genes, including the insulin receptor gene, INSR, and other genes involved in adipogenesis and beta-cell insulin secretion. In this context, recently our group has identified a new gene involved in the pathogenesis of insulin resistance and type 2 DM: the HMGA1 gene. Functional genetic variants of the HMGA1 gene, capable of reducing the intracellular levels of INSR in insulin target tissues, were found in 10% of patients with type 2 DM in three distinct populations: Italian, North American and French.