Despite the clear relationship between HbA(1c) levels and risk of cardiovascular disease in patients with type 2 diabetes mellitus (T2DM) in epidemiologic studies, prospective data on the role of glucose-lowering therapy in reducing cardiovascular events are equivocal. Initial studies of intensive glycemic control suffered from inadequate statistical power to show reductions in cardiovascular events, as well as a lack of durable glycemic control and relatively poor control of associated cardiovascular risk factors. Subsequently, controversy existed over whether rosiglitazone was associated with an increased risk of myocardial ischemic events. Large, prospective, cardiovascular outcome trials that assessed intensive glycemic control versus standard glycemic control have had disappointing results; however, cardiovascular event rates seem to be declining substantially in patients with T2DM managed with aggressive global cardiovascular risk factor modification, which might have masked the benefits of glycemic control. Individuals with T2DM without a history of cardiovascular disease, as well as younger individuals with more modest elevations of HbA(1c), may benefit from a more intensive glucose-lowering strategy. A comprehensive and multifactorial intervention strategy that includes aggressive glycemic control, blood-pressure-lowering and lipid-lowering therapy, aspirin use and lifestyle modifications is beneficial in reducing both macrovascular and microvascular events in patients with T2DM.