In patients with sepsis and SIRS, the liver has two opposing roles: a source of inflammatory mediators and a target organ for the effects of the inflammatory mediators. The liver is pivotal in modulating the systemic response to severe infection, because it contains the largest mass of macrophages (Kupffer cells) in the body; these macrophages can clear the endotoxin and bacteria that initiate the systemic inflammatory response. This article summarizes the functional changes that take place in the liver during sepsis and systemic inflammatory response syndrome and discusses the cellular and molecular mechanisms that underlie clinical outcomes.