Sulfonylureas have represented the backbone of oral therapy in non-insulin-dependent diabetes mellitus for > 30 yr. Despite this, our knowledge about the mode of actions of these agents is limited, and the use of them is far from rational. Sulfonylureas lower blood glucose concentrations primarily by stimulating insulin secretion. The evidence for clinically significant extrapancreatic effects is scanty. Therefore, the effect of sulfonylurea is limited to patients with preserved β-cell function, with the best effect observed in the early stages of the disease. Sulfonylurea treatment is often started relatively late and is continued when the agents can no longer achieve the treatment goals. Drug dosages are increased to maximum recommended doses, although there is no evidence for a dose-response relationship between the sulfonylurea dose and its biological effect. To rationalize the use of sulfonylureas, we should ask the questions to whom, how much, and for how long? The decision to stop treatment is as important as the decision to start treatment.