Diabetes mellitus is a major risk factor for cardiovascular disease and mortality. Diabetic patients have a two- to fourfold increased risk of developing cardiovascular disease. There is convincing evidence that tight glycemic control aimed at lowering HbA(1c) reduces cardiovascular risk. However, even well-controlled diabetic patients remain at increased risk. The reason is that, although antihyperglycemic agents have been available for many years, we have been unable to mimic physiological insulin secretion. Type 2 diabetic patients typically lose the first phase of insulin secretion very early in the course of their disease, resulting in increased postprandial glucose excursions (PPGEs). This has, until recently, been largely neglected. This review will discuss the physiological control of postprandial glucose, as well as the causes of increased PPGEs and of other features of postprandial dysregulation seen in subjects with abnormal glucose tolerance. It will also discuss the effects of increased PPGE on the endothelium and review the epidemiological data linking postprandial hyperglycemia to cardiovascular disease. Finally, the effectiveness of a number of therapeutic options in lowering postprandial glucose and their effect on the endothelium and outcome will be reviewed. However, the possible role of PPG in cancer risk and in cognitive function is beyond the scope of this review and will not be discussed.