It is well-established that reperfusion is the major method of salvaging ischemic myocardium following prolonged coronary artery occlusion, although the idea of reperfusion injury remains controversial. Moreover, more recent evidence strongly suggests that reperfusion per se is thought to result in further damage to the myocardium and blood vessel endothelium by various biochemical and physical factors including a burst of oxygen-derived free radicals (ROS), cellular or mitochondrial calcium overload and shear stress, to name a few. This has been termed lethal reperfusion injury. It has become increasingly evident that strategies in which interventions are administered during the early stages of reperfusion produce a reduction in reperfusion-mediated damage primarily by reducing massive calcium overload or by altering the intracellular milieu (pH, osmotic stress, etc.) and ROS release upon reperfusion. Furthermore, it is apparent that activation of blood borne elements such as neutrophils and macrophages and factors released by these cells such as cytokines may be responsible for a continuing expansion of infarction in the hours or even days following timely reflow and that inhibiting these factors may attenuate reperfusion injury. The present review will focus on the effect of endogenous and exogenous opioids on ischemic and reperfusion injury since these compounds are routinely used in the surgical arena and may have unappreciated cardioprotective effects in this subset of patients. Particular emphasis will be on the role of opioids in reperfusion injury and their relationship to the newly discovered phenomenon of postconditioning.