Myocardial ischemia is a major cause of morbidity and mortality in the world. Although restoration of blood flow after prolonged ischemia is essential for cardiomyocytes salvation and to limit myocardial damage and cardiac dysfunction, reperfusion itself exacerbates myocardial injury. Considerable evidence attributes reactive oxygen species (ROS), produced either by the myocardium itself or by infiltrating inflammatory cells, as an early event in this process. Once produced, ROS can lead to cellular damage through a number of pathways including direct damage to membranes and proteins or indirect damage through the activation of pro-apoptotic pathways. While using antioxidants to scavenge free radicals or targeting the sources of ROS, such as xanthine oxidase, may be potential attractive approaches to reduce myocardial reperfusion injury, clinical trials using antioxidant therapies have been largely disappointing. Neither oxidant scavengers like N-acetylcysteine and vitamins E and C, nor xanthine oxidase inhibitor allopurinol have provided indisputable evidence of a clinical benefit despite numerous favourable studies in animal models. Evidence to support a role of ROS in myocardial injury reperfusion is strong, but the clinical approach used has so far been inadequate. Absence of optimal pharmacology, variation in end-points used and low specificity of the compounds used have often been pointed out. In addition, the efficacy of antioxidants is often evaluated based on indirect biomarkers, which are prone to variation. Thus, clinical trials could be improved by the standardisation of the methods to measure oxidative stress and their impact on prognosis outcome.