The incidence of mortality in acute renal failure (ARF) induced by ischemia-reperfusion (I/R) injury or septic shock is high. Previous studies using animal models of ARF reported that inflammation-induced macrophage recruitment in endothelial cells, along with I/R-induced production of inflammatory cytokines and chemokines in tubule epithelial cells, results in macrophage and neutrophil accumulation, and that both ultimately lead to irreversible kidney injury. Recent studies suggest that ARF may also induce a beneficial stress response program and express many transcriptional regulators, including activating transcription factor 3 (ATF3). ATF3 is a member of the ATF/CREB subfamily of the basic-region leucine zipper (bZIP) family. Recent research has shed new light on the protective role of the ATF3 signaling pathway in attenuating inflammation and I/R-induced tubular cell death and nephrotoxicity. A recent clinical study also reported that ATF3 can serve as an indicator of acute kidney injury (AKI). AKI is associated with a robust inflammatory effect with increased levels of cytokines, including IL-6, IL-12, and IFNγ. By inhibiting these cytokines, the ATF3 molecule may hold the potential to provide future epigenetic therapy against inflammation-induced renal injury.