In 1942 Janbon described the hypoglycemic action of sulfonamides; however, the implications for the treatment of diabetes were ignored because of World War II until research by Franke and Fuchs on carbutamide established its hypoglycemic action. Because of toxic side effects, carbutamide did not prove to be useful; however, further research led to the development of the related compound tolbutamide, the first of many sulfonylureas used to treat non–insulin-dependent diabetes mellitus (NIDDM). From 1955 to 1995 in the United States, the pharmacologic options available for the treatment of NIDDM were limited to sulfonylureas and insulin injections. Since then, the therapeutic options have expanded significantly and will continue to expand if medications currently under investigation fulfill their early promise. The sulfonylureas have demonstrated an ability to achieve acceptable glycemic control in many patients with NIDDM, and the availability of new medications should not lead to an abandonment of their use without good cause. On the other hand, lingering concerns about the effectiveness and safety of the sulfonylureas have led to eager acceptance of the newly available medications. The introduction of the new medications prompts a reevaluation of the therapeutic role of sulfonylureas.