Sepsis and aminoglycoside administration remain leading causes of clinical acute renal failure (ARF). In recent years, a number of experimental studies from different laboratories have indicated that specific components of the septic state, most notably fever, endotoxemia, and renal hypoperfusion, can interact to induce synergistic renal damage, acting in concert to produce acute tubular necrosis and ARF. If sepsis-associated ARF has a multifactorial basis, then a number of interventions directed at one or more of its etiologic components could confer protection. In this brief review, evidence to support these pathophysiological and therapeutic considerations are presented.