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Toxic factors released from the intestine have been implicated in the pathophysiology of severe acute illness, including acute pancreatitis, trauma and hemorrhagic shock, and burns. Toxic factors in mesenteric lymph may induce an inflammatory systemic response while bypassing the portal circulation and liver. This paper reviews current knowledge of the anatomy, physiology and pathophysiology of mesenteric lymph and focuses on factors influencing its composition and flow, and potential therapeutic interventions. A search of the Ovid MEDLINE database up until the end of January 2006 yielded 1,761 relevant publications, the references of which were then searched manually to identify further related publications. A wide range of factors potentially affecting mesenteric lymph flow and composition were identified. Targeted interventions have been similarly broad, including medical therapy, nutritional support and surgery. Of the available surgical interventions, thoracic duct external drainage has been the most widely studied. This systematic review highlights significant gaps in our present understanding of the role of mesenteric lymph in health and disease. Further research is needed to identify factors responsible for the generation of biologically active mesenteric lymph, the role of agents modulating its flow and composition, the importance of intrinsic pump activity, the potential therapeutic role of lipophilic antioxidant agents, the comparative effects of low-fat enteral nutrition and standard enteral nutrition, and the therapeutic outcomes of thoracic duct ligation versus thoracic duct external drainage.