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Acute renal failure is a serious condition that affects as many as 20% of ICU patients. The most common causes of acute renal failure in the ICU patient are severe sepsis and septic shock. The mortality of acute renal failure in septic critically ill patients remains high despite our increasing ability to support vital organs. This is partly the result of our poor understanding of the pathogenesis of sepsis-induced renal dysfunction. Accordingly, a review of our current understanding of the pathogenesis of septic acute renal failure is timely and relevant.Throughout the past half century, acute renal failure of acute illness has essentially been considered a hemodynamic disease caused by kidney ischemia, a view derived by findings in animal models. Unfortunately most such models are greatly deficient in that they do not reproduce the high cardiac output, low systemic vascular resistance state typically seen during human sepsis. Furthermore, most models inducing so-called acute tubular necrosis are based on ischemia–reperfusion (renal artery clamping), an event with little relevance to human sepsis. Recent research highlights a new possible and emerging concept for the pathogenesis of septic acute renal failure: acute apoptosis. This concepts fits well with the typical paucity of histologic changes seen in so-called acute tubular necrosis and with growing evidence of a role for apoptosis in organ injury during sepsis and inflammation in general. Furthermore, the authors present evidence that some potential treatments recently shown to affect the mortality of critically ill patients, (activated protein C, intensive insulin treatment, and low-volume mechanical ventilation) might have antiapoptotic activity.This review suggests that, on the evidence available, septic acute renal failure is more likely to be an immune or toxic state rather than simply a hemodynamic condition. The authors speculate that future insights into its pathogenesis might lead to a paradigm shift away from the concept of acute tubular necrosis, which has never been convincingly shown in sepsis, to that of acute tubular apoptosis.