Ischemic heart disease is the leading cause of morbidity and mortality in diabetes. Patients with diabetes are particularly at risk of perioperative myocardial infarction, and are less resistant to myocardial ischemia-reperfusion injury (IRI), but the underlying mechanisms are very unclear. Opioid conditioning has been well demonstrated to be protective against myocardial IRI like ischemic conditioning, but this effect is compromised in diabetic condition, and little is known about the role of opioid-induced cardioprotection during diabetes. This brief review is to provide a summary of our present understanding of the effects of diabetes on opioids induced protection against myocardial IRI and the challenges of limiting IRI by opioids in the diabetic heart.