The University Group Diabetes Program (UGDP), launched in 1960, was an early placebo-controlled, multi-center clinical trial devised to determine which, if any, of the treatments for type 2 diabetes was efficacious. Because of an excess of cardiac deaths in patients treated with tolbutamide, a sulfonylurea drug, investigators terminated this limb of the study. This decision was met with strong resistance from the parent drug company and many in the medical community. Subsequent clinical studies both supported and conflicted with the UDGP findings, so that the controversy has persisted. A rationale for sulfonylurea-induced cardiotoxicity emerged with the observation that these drugs block ischemic preconditioning, a protective maneuver that reduces myocardial damage after temporary blockage of coronary blood flow; this action of sulfonylureas provided laboratory support for the UGDP findings. The development of newer sulfonylurea drugs that do not block ischemic preconditioning has rendered the UGDP controversy moot and has preserved a place for sulfonylureas in the treatment of type 2 diabetes.