In type 2-diabetes and impaired glucose tolerance, the muscle, fat and liver become resistant to insulin, and recent developments place dysregulation of insulin receptor substrate (IRS) expression and activation at the center of such defects. IRS1 and IRS2 are the major insulin receptor substrates leading to glucose homeostasis, and have distinct and overlapping roles in diverse organs. The majority of the published literature in this field suggests that IRS1 is the major substrate leading to stimulation of glucose transport in muscle and adipose tissues, whereas in liver, IRS1 and IRS2 have complementary roles in insulin signaling and metabolism.