Sulfonylureas seem to have similar mechanisms of action, including an acceleration and increase of insulin secretion, an increase of the systemic availability of insulin, and probably indirectly, an increase of insulin action. Sulfonylureas may postpone the development of impaired glucose tolerance (IGT) to manifest non-insulin-dependent diabetes mellitus (NIDDM), and all NIDDM subjects should benefit from sulfonylurea treatment except those in whom insulin secretion has been attenuated. The most effective use is the combination of diet restriction and sulfonylurea introduced in NIDDM subjects soon after transition from IGT to NIDDM. A simple screening procedure has been devised to find the subjects at this early stage. Newer sulfonylureas, such as glipizide and glyburide, are more potent than the older ones, such as tolbutamide and chlorpropamide. During chronic treatment, glipizide and glyburide seem to be equally effective in reducing blood glucose levels, and they do so without causing a chronic elevation of insulin secretion, signifying that they do not increase the risk of pancreatic B cell exhaustion. Glipizide has rapid and complete absorption, as well as a rapid distribution and elimination. This may explain why it is less liable than other sulfonylureas to provoke long-lasting hypoglycemia, which is the major danger when using sulfonylureas. Despite its rapid elimination, 7.5 to 15 mg glipizide can be administered once daily without loss of therapeutic efficacy. This may be due in part to enterohepatic recirculation of the drug in response to meals. The therapeutic efficacy is increased if glipizide is received half an hour before breakfast.