Chronic hyperglycemia, as assessed by hemoglobin A1c (HbA1c) levels, has been associated with the development of microvascular and macrovascular complications of diabetes. Several studies have shown that acute hyperglycemia can add to the effect of chronic hyperglycemia in inducing tissue damage. Acute hyperglycemia can activate the same metabolic and hemodynamic pathways as chronic hyperglycemia. In particular, it is associated with increased mitochondrial production of reactive oxidant species, which have been suggested as the link between hyperglycemia and the activation of downstream pathways, mediating tissue damage. Studies performed in subjects with diabetes have shown that there is a positive association between HbA1c and both fasting and postprandial glucose levels. However, it appears that the contribution of these two parameters to the total HbA1c concentrations varies according to the degree of metabolic control. Postprandial glucose excursions are predominant in patients with a good or mild glycemic control, whereas the contribution of fasting hyperglycemia is stronger as glycemic control worsens. Glucose variability, like the intra-day glucose fluctuations from peaks to nadirs, is another important parameter, which, mainly in subjects with type 2 diabetes, has emerged as an HbA1c-independent risk factor for the development of vascular complications. Based on the current knowledge on the association not only of HbA1c, but also of fasting and postprandial glucose, with diabetes complications, it is paramount that antidiabetes strategies are directed at improving all these components in order to reduce the burden associated with diabetes.