The liver has a unique role in regulation of blood glucose in the postabsorptive state, after ingestion of glucose-containing meals, and in circumstances of glucopenia. It is soley responsible for the delivery of glucose to the bloodstream in the fasted state, thereby maintaining blood glucose concentration for the ongoing needs of body tissues, particularly the brain. An equally important role is played by the liver in the maintenance of normal glucose tolerance in response to carbohydrate ingestion. The liver is the principal site of glucose deposition after glucose feeding, while muscle and adipose tissue represent relatively minor sites of disposal of ingested glucose. In addition, the rise in glucose and insulin caused by glucose ingestion inhibits endogenous hepatic glucose production, which serves to minimize postprandial elevations in blood glucose. When blood glucose is reduced by small increments in circulating insulin, a rebound increase in glucose output from the liver is the initial or principal mechanism counteracting the fall in blood glucose concentration. Studies in juvenile-onset diabetes indicate that the liver is capable of altering its release of glucose in response to changes in blood glucose concentration when small, physiologic doses of insulin are infused. These findings may provide an explanation for the efficacy of preprogrammed insulin delivery systems in the treatment of diabetes.