The hypoglycemic effect of sulfonylureas and their analogues results from their binding to a high affinity site in the B-cell plasma membrane. This site seems to be a structural component of the ATP-sensitive K(+)-channel and represents the pancreatic sulfonylurea receptor. Binding of sulfonylureas causes closure of the ATP-sensitive K(+)-channel and thereby initiates a chain of events eventually leading to the release of insulin. Diazoxide inhibits insulin secretion via opening of the ATP-sensitive K(+)-channel. Sulfonylurea receptors resembling the pancreatic receptor occur in nerve cells, cardiac muscle, skeletal muscle and smooth muscle. Neither these extrapancreatic receptors nor low affinity receptors for sulfonylureas in myocytes and adipocytes contribute to the therapeutic benefit of sulfonylureas.