Abstract: Diabetes Mellitus has a high morbidity and correlates with many other diseases. When associated with diabetes mellitus, ischemic heart disease (IHD) tends to induce myocardial ischemia/reperfusion injury (MI/RI). Oxidative stress plays a key role in affecting both metabolic disorder and MI/RI. Altered lipid metabolism, endothelial dysfunction, and APN resistance in the presence of increased cardiomyocyte apoptosis, decreased antioxidant defense, and impaired prosurvival cell signals may render the diabetic heart more vulnerable to MI/RI. Producing reactive oxygen species (ROS) and reactive nitrogen species (RNS), uncoupling nitric oxide synthase (NOS) and disturbing the mitochondrial quality control may be three major mechanisms of oxidative stress. This review focuses on the role of oxidative stress in the pathophysiology of MI/RI in diabetes mellitus and discusses potential mechanisms in an effort to provide some evidence for oxidative stress-targeted therapies for IHD.