Accumulating experimental and clinical evidence suggests a major impact of reperfusion injury mediated by reactive oxygen species (ROS) on the development of chronic allograft dysfunction. The underlying mechanisms by which this nonspecific injury contributes to the initiation and progression of chronic allograft dysfunction are not fully understood. Three pathways are addressed in this article: 1) a ROS-mediated disturbance of the microcirculation in renal allografts, which may contribute, in addition to the existence of anaerobic metabolism, to delayed graft function as a risk factor for chronic dysfunction; 2) a ROS-mediated acute endothelial injury at the allograft vessel walls, which leads, in analogy to the response-to-injury hypothesis, to alloatherogenesis as a characteristic sign of chronic allograft dysfunction; and 3) a ROS-mediated global injury to the allograft, which represents, in analogy to the danger hypothesis, the primary key event that initiates alloimmune responsiveness via T-cell activation by facilitating costimulatory processes. These clinically manifesting or subclinically occurring immune events, which are initiated by reperfusion injury as the driving force, contribute specifically to development of chronic allograft dysfunction.