In as many as 50% of cases the immediate post-kidney transplant course is complicated by delayed graft function that is most commonly related to ischemia and reperfusion injury. In addition to the acute complications related to renal failure and the associated economic impact of prolonged hospitalization, the development of delayed graft function is associated with an increased risk of chronic allograft nephropathy and shortened allograft survival. Challenges in understanding its mechanisms include the complexity, as contributors are derived from both the donor and the recipient. This acute kidney injury is modulated and caused by a complex interplay of events that lead to hypoxic and ischemic injury as well as to altered repair mechanisms. New therapies primarily seek to suppress the inflammatory homing of adaptive immune cells to the kidney, limit cell death, and/or interrupt detrimental signaling of necrosis. Although there are several promising novel targets and innovative therapeutics available, many challenges remain in their translation from bench to bedside. Identifying organs at risk and clearly defined end points will be critical in designing interventional trials.