Ischemia-reperfusion injury occurs in many organs and is the underlying cause of many disease processes, including myocardial infarction, stroke, and acute renal failure, which in total are responsible for the majority of deaths seen in developed countries. Most of the injury seen with this process is associated with the reperfusion phase in which the blood flow to the ischemic tissues is reinstituted. This reperfusion phase is associated with the formation of reactive oxygen species (ROS) in the tissues, and the sources of these oxidants are both the neutrophil as well as parenchymal cells such as endothelium. In the kidney as well as other organs, antioxidant therapy is protective, suggesting an important role for these agents. However, there is emerging evidence that ROS are not solely responsible for the reperfusion injury. In many of the kidney models of ischemia-reperfusion, antioxidants are only partially effective in ameliorating the functional and morphologic alterations. Furthermore, in vitro, ROS do not appear to be primarily involved in the killing of renal tubular epithelial cells, which is the morphologic hallmark of acute renal failure. Thus, reperfusion injury, like other types of tissue injury, appears to be mediated by more than one class of inflammatory mediator.