Diabetes mellitus is a world-wide health issue with potential for significant negative health outcomes, including microvascular and macrovascular complications. The relationship of hemoglobin HbA1c and other glycosylation end products (AGEs) to these complications, particularly microvascular disease, is well understood. More recent evidence suggests that glycemic variability may be associated with diabetes macrovascular complications. As HbA1c is better representative of average glucose levels and does not account as well for glycemic variability, hence new methods to assess and treat this variability is needed to reduce incidence of complications. In this chapter, the relationship of glycemic control to diabetes complications will be explored with focus on the mechanisms of tissue damage from this variability along with the oxidative stress. Additionally, treatment strategies to optimize HbA1c and glycemic variability with the goal of reducing risk of complications in persons with diabetes are reviewed.