Pathologic increases in intestinal permeability to hydrophilic macromolecules has been identified in a number of clinical conditions. The significance of gut barrier dysfunction as a clinical issue remains to be delineated, although it seems likely that alterations in intestinal epithelial permeability play a causative role in a number of conditions ranging from inflammatory bowel disease to the development of complications after cardiopulmonary bypass. It is unlikely that any one mechanism can account for all cases of intestinal hyperpermeability. Rather, it is more probable that myriad factors or combinations of factors, including mesenteric ischemia and cytokine-induced phenomena, lead to alterations in permeability in different clinical entities. Nevertheless, from a purely mechanistic standpoint, some common themes, notably the role of ATP depletion, increases in [Ca2+]i, and cytoskeletal derangements in enterocytes, have emerged as being particularly important.