Acute renal failure induced by renal ischemia or drugs continues to be a relevant clinical problem. Li et al. have demonstrated that proximal tubule-restricted peroxisome proliferator-activated receptor-alpha (PPARalpha) expression in transgenic mice reduced cisplatin- and ischemia/reperfusion-induced acute renal injury. Their article suggests a role for the maintenance of free fatty acid oxidation in the proximal tubule as a mechanism of nephroprotection, as well as a potential clinical utility of PPARalpha activators in the prevention of acute renal failure.