The central concept of this review is that gut-derived factors contained primarily in the mesenteric lymph rather than the portal blood contribute to distant organ injury. This hypothesis is supported by recent studies indicating that division of the mesenteric lymphatic ducts prevents lung injury after hemorrhagic shock and significantly ameliorates lung injury after thermal injury. The mechanism of hemorrhagic shock-induced lung injury appears to be through mesenteric lymph-induced activation of neutrophils and activation/injury of endothelial cells. This notion is supported by in vitro studies indicating that mesenteric lymph, but not portal vein plasma, collected after a nonlethal episode of hemorrhagic shock activates neutrophils, increases endothelial cell monolayer permeability, and can even cause endothelial cell death. This concept that gut-derived factors contained primarily in the mesenteric lymph rather than the portal system potentiate the development of distant organ (lung) injury, if correct, would help clarify several important issues. First, because the lung is the first organ exposed to mesenteric lymph (i.e., mesenteric lymph enters the subclavian via the thoracic duct), it would help explain the clinical observation of why the lung is generally the first organ to fail in severely injured patients. Second, this gut lymphatic hypothesis would provide new information on the pathophysiology of gut-induced lung injury. Finally, it would help explain the discordant results between experimental and some clinical studies on the role of gut injury and loss of gut barrier function in the development of a systemic inflammatory state and distant organ injury.