Major trauma, shock, sepsis, and other conditions can lead to the acute respiratory distress syndrome (ARDS), which may progress to the highly lethal multiple organ dysfunction syndrome (MODS). Although a number of therapeutic strategies have been initiated, their success has been limited largely due to an incomplete understanding of the biology of MODS. However, recent studies indicate that the intestinal lymphatics serve as the primary route for nonbacterial, tissue injurious gut-derived factors, which can induce acute ARDS and MODS. The gut lymph hypothesis of ARDS and MODS thus helps clarify several important issues. First, because the lung is the first organ exposed to mesenteric lymph and not the liver (i.e., mesenteric lymph enters the subclavian vein via the thoracic duct, which, in turn, empties directly into the heart and lungs), it would explain the clinical observation that the lung is generally the first organ to fail. Second, this hypothesis provides new pathophysiologic information, thereby providing a basis for novel therapies. Finally, by studying the composition of lymph, MODS-inducing factors can be isolated and identified.