Insulin receptor substrate (IRS) molecules are key mediators in insulin signaling and play a central role in maintaining basic cellular functions such as growth, survival, and metabolism. They act as docking proteins between the insulin receptor and a complex network of intracellular signaling molecules containing Src homology 2 (SH2) domains. Four members (IRS‐1, IRS‐2, IRS‐3, IRS‐4) of this family have been identified that differ as to tissue distribution, subcellu‐lar localization, 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 to the functional differences among these related molecules, suggesting they play different and specific roles in vivo. The available data are consistent with the notion that IRS‐1 and IRS‐2 are not functionally interchangeable in tissues that are responsible for glucose production (liver), glucose uptake (skeletal muscle and adipose tissue), and insulin production (pancreatic β cells). In fact, IRS‐1 appears to have its major role in skeletal muscle whereas IRS‐2 appears to regulate he‐patic insulin action as well as pancreatic β cell development and survival. By contrast, IRS‐3 and IRS‐4 genes appear to play a redundant role in the IRS signaling system. Defects in muscle IRS‐1 expression and function have been reported in insulin‐resistant states such as obesity and type 2 diabetes. Several polymorphisms in the IRS genes have been identified, but only the Gly→Arg⁹⁷² substitution of IRS‐1, interacting with environmental factors, seems to have a patho‐genic 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.—Sesti, G., Federici, M., Hribal, M. L., Lauro, D., Sbraccia, P., Lauro, R. Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. FASEB J. 15, 2099–2111 (2001)