Background: Despite increased understanDing of the pathophysiology of septic acute kidney injury (AKI), treatment options are limited, and mortality remains high. Summary: Septic AKI is triggered by pathogen-associated molecular patterns from bacteria and damage-associated molecular patterns released from or exposed on damaged cells. Downstream effects include glomerular and peritubular endothelial dysfunction, downregulation of tubular reabsorptive work, cell-cycle arrest, regulated cell death and destruction of damaged cell organelles. In the laboratory, pharmacological modulation of some of these pathways prevents AKI or enhances recovery from AKI, yet no data exist to support the utility of such AKI therapy in man. However, avoiDing systemic and renal venous congestion, hypotension and fluid overload attenuates AKI in critically ill septic patients. Key Message: While therapies aiming at modulating the sepsis-induced cellular response are discovered and tested, hemodynamic optimization remains critical in patients with or at risk of AKI.