Erythropoietin (EPO) has traditionally been viewed as a hormone dedicated to the regulation of erythropoiesis. More recently, the EPO receptor (EPOR) has been found to be expressed in a large variety of non-haematopoietic tissues suggesting that EPO might have important actions beyond erythrocyte production. Over the last five years, short-term, high dose administration of EPO has been shown to ameliorate acute kidney injury (AKI), as evidenced by suppressed tubular epithelial apoptosis, enhanced tubular epithelial proliferation, and hastened functional recovery. This renoprotective effect is still apparent when administration is delayed up to 6 hours after the onset of injury and has been demonstrated in a variety of animals (mouse, rat, dog, pig) in response to a variety of renal insults (ischaemia-reperfusion injury, cisplatin, ureteral obstruction, cyclosporine, radiographic contrast, endotoxaemia, heat-shock, and aristolochic acid). Based on these highly encouraging results, several large randomised controlled trials of EPO therapy in ischaemic or toxic AKI are currently underway. The purpose of this article is to review the experimental and clinical evidence for a renoprotective benefit of EPO in acute kidney injury (AKI), the potential mechanisms underpinning these renoprotective actions and possible future directions for research in this important area.