There is considerable evidence that hyperglycemia represents the main cause of complications of diabetes mellitus (DM), and oxidative stress resulting from increased generation of reactive oxygen species plays a crucial role in their pathogenesis. In fact, in the absence of an appropriate response from endogenous antioxidant mechanisms, the redox imbalance causes the activation of stress-sensitive intracellular signaling pathways. The latter play a key role in the development of late complications of DM, as well as in mediating insulin resistance (i.e., resistance to insulin-mediated glucose uptake by some cells) and impaired insulin secretion. This review, focused on lipid peroxidation in DM, will examine the mechanisms and clinical readouts of oxidative stress in this setting, the relationship between lipid peroxidation and antioxidant status in type 1 and type 2 DM, the effects of hyperglycemia and metabolic control on in vivo markers of lipid peroxidation (i.e., isoprostanes), and the association between isoprostane formation and platelet activation. Finally, possible targets of antioxidant therapy for diabetic vascular complications will be discussed.