Ischemia-reperfusion injury to the kidney is a complex pathophysiological process that has importance during transplantation as it affects graft function and survival. It starts with the physiological changes associated with the death of the donor, including the direct effects of hypoxia and metabolic stress. The injury continues through the organ procurement and preservation procedures. Upon reperfusion, the organ is then further damaged by a reactive inflammatory process which had been primed during the earlier injuries. Clinically, the damage from microvascular dysfunction and cytotoxic agents contributed by the immunologic response results in impaired graft function or graft loss. Recent advances in understanding the specific pathways involved in this injury have helped identify novel therapies. Nevertheless, ischemia-reperfusion injury continues to be a daunting problem even as these treatment strategies are being evaluated for clinical use.