Hyperglycemia is the cause of chronic microvascular complications in diabetes. Increased macrovascular disease occurring in diabetes is multifactorial, with hyperglycemia being only 1 of the factors responsible. A major deficiency in our understanding of the role of hyperglycemia in the pathogenesis of chronic diabetic complications is the contribution made by exaggerated postprandial glycemic excursions, in contrast to that made by chronic fasting hyperglycemia. Hyperglycemia is thought to cause chronic diabetic complications through ≥1 of the following biochemical mechanisms: (1) an exaggerated polyol pathway, (2) protein glycation and the formation of advanced glycation end products, (3) excessive activation of protein kinase C (PKC) isoenzymes in vascular and mesangial cells, and (4) greater oxidative stress. The focus of this article is how postprandial hyperglycemia and glucose excursions might specifically activate ≥1 of these mechanisms and how they might contribute to the development of the chronic complications of diabetes by causing endothelial dysfunction, a procoagulant state, carbonyl stress, and/or vascular and oxidative effects secondary to PKC activation.