INSULIN receptor substrate-1 (IRS-1) is the major substrate of insulin receptor and IGF-1 receptor tyrosine kinases; it has an apparent relative molecular mass of 160-190,000 (M(r), 160-190K) on SDS polyacrylamide gel(1-3). Tyrosine-phosphorylated IRS-1 binds the 85K subunit of phosphatidylinositol 3-kinase(4,5) which may be involved in the translocation of glucose transporters(6,7) and the abundant src homology protein (ASH)/Grb2(8,9) which may be involved in activation of p21(ras) and MAP kinase cascade(10). IRS-1 also has binding sites for Syp(11) and Nck(12) and other src homology 2 (SH2) signalling molecules. To clarify the physiological roles of IRS-1 in vivo, we made mice with a targeted disruption of the IRS-1 gene locus. Mice homozygous for targeted disruption of the IRS-1 gene were born alive but were retarded in embryonal and postnatal growth. They also had resistance to the glucose-lowering effects of insulin, IGF-1 and IGF-2. These data suggest the existence of both IRS-1-dependent and IRS-1-independent pathways for signal transduction of insulin and IGFs.