The paracellular route is the dominant pathway for passive solute flow across the intestinal epithelial barrier, and its permeability depends on the regulation of intercellular tight junctions (TJs), also known as the zonula occludens. As a barrier between apical and basolateral compartments, TJs selectively control the passive diffusion of ions and small water soluble solutes from the intestinal lumen to the bloodstream through the paracellular pathway, thereby counterregulating any gradients generated by transcellular pathways.1 Variations in transepithelial conductance can usually be attributed to changes in the permeability of the paracellular pathway as the resistance of the plasma membrane of the cell is relatively high.2 The TJ represents the major barrier within this paracellular pathway and the electrical resistance of the intestinal mucosa seems to depend on the number of transmembrane protein strands and their complexity within the TJ, as observed by freeze fracture electron microscopy. A century ago, TJs were conceptualised as a secreted extracellular cement forming an absolute and unregulated barrier within the paracellular space.3Biological studies of the past several decades have shown that TJs are dynamic structures subjected to structural changes that dictate their functional status under a variety of developmental,4-6physiological,7-10 and pathological circumstances.11-13 To meet the many diverse physiological challenges to which the epithelial and endothelial barriers are subjected, TJs must be capable of rapid and coordinated responses. This requires the presence of a complex regulatory system that orchestrates the state of assembly of the TJ multiprotein network. While our knowledge on TJ ultrastructure and intracellular signalling events have significantly progressed during the past decade, relatively little is known about their pathophysiological regulation secondary to extracellular stimuli. Therefore, the intimate pathogenic mechanisms of diseases in which intestinal permeability is affected and the utility of TJ modulation for drug delivery …