Despite the availability of renal replacement therapy, acute kidney injury (AKI) is associated with high mortality and morbidity. In humans, it is difficult to determine whether AKI is a cause or consequence of excess morbidity. In animal models, however, it is increasingly clear that AKI induces distant organ dysfunction. Identified pathways include inflammatory cascades, apoptosis, the induction of remote oxidative stress, and differential molecular expression. Specifically, growing evidence implicates renal injury as an instigator and multiplier of pulmonary, cardiac, hepatic, and neurologic dysfunction. Accurate identification of these pathways will be critical in developing targeted therapies to improve outcomes in AKI. The purpose of this review is to summarize both clinical and preclinical studies of AKI and its role in distant organ injury.