Plasma glucose concentration is a major regulator of glucose production in experimental animals and in humans. Hyperglycemia inhibits and hypoglycemia stimulates glucose production through mechanisms which are, in part, independent of changes in glucoregulatory hormones. Glucose production does not change when gluconeogenesis is acutely inhibited or stimulated. These observations indicate an autoregulatory process by which hepatic glucose production is altered as a direct consequence of changes in glycemia. Data obtained in patients with glucokinase gene mutations indicate that glucokinase may play a role in this regulatory process. Hyperglycemia in type 2 diabetic patients and in critically ill patients may result from a blunted effect of hyperglycemia on glucose production.