Oxidative stress has been repetitively shown to be a hallmark of many diseases linked with metabolic or vascular disorders. Therefore diabetes represents an ideal candidate for studying the consequences of oxidative stress and its treatment. Indeed diabetes constitutes a multiple source of free radicals, starting very early in the disease process and worsening over the course of disease. In view of the typical characteristics of diabetes, oxidative stress is expected to have a double impact, on both metabolic and vascular functions. It is therefore particularly disappointing to note the dramatic failure of clinical trials with antioxidants, although it must be pointed out that such studies have not been performed with only diabetic patients. This review describes the many different aspects of oxidative stress in diabetes and proposes possible explanations for the apparent lack of efficacy of antioxidant treatments in patients. Some verifications seem warranted before a definitive conclusion can be drawn about the validity of this therapeutic concept.