The sequence of events in heart ischemia-reperfusion has been clearly documented in experimental animal models but not in cardiac surgery patients. The evidence in human studies had not been gathered in a systematic and comprehensive fashion, so as to provide an encompassing picture of the phenomenon. This limits our ability to devise appropriate strategies for optimal perioperative myocardial protection. We present here a review or our experience in myocardial ischemia-reperfusion in a historical perspective. From our previous studies we conclude that, although several issues still remain unsolved, there is no doubt that oxygen-free radicals are important contributors to myocardial injury during the reperfusion period of coronary artery bypass surgery. Yet, in spite of this wealth of information, both clinical and experimental, subsequent clinical trials conducted over the last several years with a variety of antioxidant strategies have been largely disappointing. Therefore, the whole paradigm of oxidative stress in cardiac injury needs to be re-evaluated. In this regard, differences between past and current knowledge are discussed, and future directions are traced. We concluded that patients subjected to elective bypass surgery undergo oxidative stress upon reperfusion after cardioplegic arrest; the magnitude of the phenomenon, however, is at present small and may not justify widespread antioxidant therapy.