Improving the ability of the kidney to tolerate injury through preconditioning is likely to have important clinical implications. Although a number of preconditioning strategies have been studied, ischemic preconditioning (IP) has been studied the most experimentally. The information gathered has helped us shed more light into the mechanisms responsible for this tissue adaptation that confers to tissues a more resistant status. IP is effective within minutes, suggesting that preformed mediators are involved. This is followed by delayed preconditioning, a phenomenon that is less potent but longer acting. Remote preconditioning occurs also in non-affected tissues and can be transferable. A number of mediators and transcription factors have been implicated including kinases, heat shock proteins, nitric oxide and neurogenic pathways, all of which help change the cell into a more resistant phenotype. There is evidence that IP also occurs in the human environment with lessons learned from myocardial ischemia, hepatic resection and cerebral ischemia. Because of the ethical impediment with intentionally applying organ ischemia, there has been an interest in pharmacological preconditioning lately. Exogenously administered erythropoietin was shown to benefit kidneys subjected to different insults. In addition, mesenchymal stem cells-based approaches for the prevention and treatment of acute kidney injury (AKI) are being studied. Calcineurin inhibitors may represent a viable way to reduce ischemia reperfusion injury in transplantation. Translating the experimental findings to the clinical arena remains a challenge. The discovery of new biomarkers for AKI should help initiate therapy early, when therapy could make a difference.