The multiple organ dysfunction syndrome (MODS) is the most common cause of death among patients requiring care in an ICU. There is widespread agreement that MODS is the clinical manifestation of a dysregulated inflammatory response. This article, however, summarizes some tantalizing data to support the view that derangements in the formation or function of specialized structures in epithelial cells, tight junctions, may be a key factor leading to lung, liver, gut, and perhaps kidney dysfunction associated with such conditions as sepsis and acute lung injury syndrome that are caused by dysregulated inflammatory processes.