The extrapancreatic effects of sulfonylurea drugs are reviewed. The effects discussed include insulinase inhibition, regulation of free and bound insulin, inhibition of glucose output by the intact liver, and actions upon lipid, ketone, protein, and carbohydrate metabolism. Recent studies demonstrating tolbutamide potentiation of insulin mediated 2-deoxy-D-glucose (2-DG) transport using intact mouse diaphragms are described. Many of the extrapancreatic effects have been achieved with concentrations of sulfonylurea considerably in excess of the plasma levels attained during clinical administration of these drugs. Criteria that should be fulfilled if extrapancreatic actions are to be a significant factor in the control of diabetes mellitus are suggested. Tolbutamide's potentiation of insulin action on carbohydrate transport by skeletal muscle, its potentiation of the action of insulin on the liver, and its direct hepatic action seem to fulfill these criteria.