Critical care nurses occasionally confront patient conditions that are not common. One such condition is hepatorenal syndrome (HRS). Three primary processes contribute to regional alterations in circulation in the renal and splanchnic beds. These processes include effective hypovolemia from the massive release of vasoactive mediators, thereby underfilling circulation, systemic and splanchnic vasodilation along with renal vasoconstriction, and hyperdynamic circulation. A “second-hit” hypothesis, whereby a triggering event causes intravascular volume depletion, likely initiates the development of HRS. The idea of a second hit focuses the attention of the health care team on surveillance strategies to prevent or limit HRS in patients with advanced cirrhosis and ascites. The treatment goal is to restore systemic and splanchnic vasoconstriction, while promoting renal vasodilation, balance sodium, and achieve euvolemia. The critical care nurse must maintain ongoing education to care for the patient with this complex syndrome in order to prevent complications and death.