Unlike other receptor tyrosine kinases, the insulin receptor does not bind directly and with high affinity to SH2 domain-containing signaling proteins. Instead, it utilizes docking devices or adaptors such as IRS-1, the recently cloned IRS-2, or Shc. Over the past year, several new molecules that bind to IRS-1 and IRS-2, as well as new downstream effectors, have been identified. The structures of several recognition domains of signaling molecules in the insulin pathway have also been solved. In addition, several lines of inquiry have questioned the relevance the Ras-MAP kinase pathway to the metabolic actions of insulin, as well as the connection between phosphatidylinositol-3 kinase and GLUT4 translocation. The crosstalk between the insulin and receptor tyrosine kinases signaling pathways, those of the cytokine receptor family, and the G-coupled receptors via the βγsubunits of G-proteins poses a serious challenge to our understanding of signaling specificity. Signaling kinetics and cellular compartmentalization may be important determinants of signal specificity. Finally, the targeted disruption of the insulin receptor, and of other essential components of the insulin action cascade such as IRS-1 and GLUT4, has yielded some surprises.