Diabetes is associated with many microvascular and macrovascular complications. Hyperglycemia plays a pivotal role in the development of microvascular complications, but the actual effect of hyperglycemia on the development and progression of macrovascular complications remains unclear and even somewhat controversial, particularly in type 2 diabetes. Macrovascular complications are increased in individuals with type 2 diabetes long before there is significant hyperglycemia, and in many, but not all, studies a clear association of glucose elevations and macrovascular complications cannot be shown. The complicated nature of metabolic abnormalities in type 2 diabetes and the relative role of these associated conditions in the development of macrovascular disease make definitive conclusions somewhat difficult. In spite of these considerations, there are certain aspects of hyperglycemia associated with macrovascular disease, particularly elevations of postprandial glucoses, and a number of basic mechanisms to explain these associations that could lead to the development of cardiovascular disease. Some of these basic abnormalities include activation of the sorbital pathway, oxidative stress, advanced glycation endproducts (AGE), and AGE precursors. These changes can result in many abnormalities, such as endothelial dysfunction, alteration of protein function, increased cytokine production, and glycosylation of structural proteins. These considerations suggest that hyperglycemia may play an important, but as yet not clearly defined, role in clinical macrovascular disease. Pursuant to this, several major multisite studies are currently underway to clarify the role of hyperglycemia in cardiovascular disease in type 2 diabetes.