The prevalence, incidence and mortality of all cardiovascular disorders (CVD) are two- to eightfold higher in persons with diabetes than in those without diabetes. Predicting and understanding the causes of CVD still represents an enormous challenge for clinical and basic cardiovascular science. Similarly, the fundamental mechanism by which diabetic patients are more prone to heart failure is unclear and prevention of such cardiac risk remains a major challenge for which new strategies are needed. Imbalance between free radicals and anti-oxidant defenses is associated with cellular dysfunctions leading to the pathophysiology of various diseases. Evidence suggests that diabetes is associated with a reduced overall antioxidant defense system and the increased oxidative stress. This may contribute to the pathogenesis of the diabetic complications, notably the emergence of premature atherosclerosis. The transcription factor NF-E2-related factor 2/antioxidant response element (Nrf2/ARE) regulates the expression of many detoxifying genes such as catalase, superoxide dismutase, UDP-glucuronosyltransferase, c-glutamylcysteine synthetase, NAD(P)H quinone oxidoreductase 1, glutathione- S-transferase, glutathione peroxidase-1 and heme oxygenase-1. Polymorphic effects of these antioxidant genes and their regulatory regions have higher relevancy to the susceptibility to clinical conditions such as diabetes, obesity and cardiovascular diseases. Thus, the present review aims to explore the relationship between free radicals, diabetes and its associated complications with respect to the genetic makeup of Nrf2/ARE regulated genes in an effort to expand treatment options.