Insulin receptor substrate (IRS) molecules are key mediators in insulin signalling and play a central role in maintaining basic cellular functions, such as growth, survival and metabolism. They act as docking proteins for the insulin receptor and a complex network of intracellular signalling molecules containing Src homology 2 (SH2) domains. Four members (IRS-1, IRS-2, IRS-3 and IRS-4) of this family have been identified that differ in tissue distribution, subcellular localisation, developmental expression, binding to the insulin receptor and interaction with SH2 domain-containing proteins. Results from targeted disruption of the IRS genes in mice have provided important clues as to the functional differences among these related molecules and suggest that they play very different roles in vivo. The available data are consistent with the notion that both IRS-1 and IRS-2 are important for insulin action and glucose homeostasis in vivo, whereas IRS-and IRS-4 appear to play a redundant role in the IRS signalling system. Considering their key role in both insulin action and insulin secretion, IRS-1 and IRS-2 molecules have been considered plausible candidate genes involved in the pathogenesis of Type 2 diabetes. Several polymorphisms in the IRS genes have been identified, but only the Gly --> Arg72 substitution of IRS-1, acting with environmental factors, seems to have a pathogenic role in the development of Type 2 diabetes. In contrast, polymorphisms of the other IRS genes do not appear to contribute to Type 2 diabetes.