It has long been recognized that major trauma, shock, or burn injury can lead to an acute systemic inflammatory state (SIRS) as well as the multiple organ dysfunction syndrome (MODS). Because of the high mortality rate associated with the development of MODS, for over two decades an intense effort has been devoted towards trying to unravel the underlying mechanisms of this complex syndrome. Although the gut has been implicated in the development of SIRS and MODS experimentally and clinically, its exact role in the pathogenesis of SIRS and MODS remains controversial. However, based on recent experimental evidence, it appears that unique gut-derived factors carried in the intestinal lymph, but not the portal vein, lead to acute injury- and shock-induced SIRS and MODS. These observations have led to the gut-lymph hypothesis of MODS, where gut-derived factors present in intestinal (mesenteric) lymph serve as the triggers that initiate the systemic inflammatory and tissue injurious responses observed after major trauma or episodes of shock.