Oxidative stress is a constant threat to all living organisms and an immense repertoire of cellular defense systems is being employed by most pro- and eukaryotic systems to eliminate or to attenuate oxidative stress. Ischemia and reperfusion is characterized by both a significant oxidative stress and characteristic changes in the antioxidant defense. By focusing on this antioxidant response of the cardiovascular system in the setting of ischemia–reperfusion injury, the aim of this review was threefold. First, based on recent animal experiments and clinical studies we shall discuss how endogenous antioxidants respond to oxidative stress during ischemia–reperfusion injury and highlight the results of recent trials on the ability of antioxidants to modulate ischemia–reperfusion injury. In this aspect, we will particularly focus on the emerging concept that various lines of antioxidant defenses do not act individually but are linked to each other in a systematic relationship as part of an antioxidant network. It is well known that enzymatic mechanisms are important components of the endogenous antioxidant repertoire; however, the relative importance of the different enzyme systems and isoforms has been much debated. The second part will focus on recent suggestions attributing a potentially key role of mitochondrial MnSOD in cardiac ischemia–reperfusion injury. Finally, the third part of the review will critically examine how endogenous antioxidants might regulate the complex signal transduction pathways of cellular activation with particular attention to the NF-κB and MAPK systems that appears to determine outcome of injury, survival, and adaptation.