Systemic inflammation contributes to significant morbidity in the ICU. With its ability to generate antiinflammatory acute-phase proteins, cytokines via Kupffer cells, and recently acknowledged resident lymphocytes, the liver provides a central regulatory role in inflammation. The liver has constant exposure to foreign material as a result of gut translocation and first-pass metabolism from the bloodstream. Consequently, the balance between hepatic activation and tolerance becomes an important factor in the host response to inflammation. Interventions and therapies that can assess and modulate these hepatic functions can improve outcomes for ICU patients.