Type 2 diabetes mellitus is a major and increasingly prevalent independent risk factor for cardiovascular morbidity and mortality worldwide. Glycemic control is a target of therapy and a principal marker of therapeutic success in diabetes, but whether lowering glucose is accompanied by a commensurate reduction in cardiovascular risk is a matter of ongoing controversy. It has become increasingly apparent from recent large-scale clinical outcome trials that glucose lowering is a poor predictor of cardiovascular outcome, and several instances of unexpectedly increased cardiovascular risk with antihyperglycemic drugs have sounded the alarm with regulatory agencies. This article reviews the critical facts that have led to a recent shift in the regulation of glucose-lowering drugs and makes the case for why new and existing antidiabetic medications should be assessed in clinical trials of cardiovascular outcome.