Inflammatory bowel diseases (IBD) are considered barrier diseases. After misleading initial results, the pathogenic importance of a disturbed mucosa is now widely accepted, largely because a certain percentage of first-degree relatives of patients with IBD do have permeability alterations, as assessed by oral markers. In the presence of a normal appearing gut mucosa, functional alterations of the highly dynamic inter-enterocyte tight junctions have to be considered to be responsible for the observed alterations. Indeed, various alterations of the transmembrane and intracytoplasmic proteins have been reported in IBD. An important therapeutic goal is to maintain disease remission by preservation of the correct organization of these complexes. Of the potential therapeutic approaches, the various anti-TNF agents are the best-studied agents, but other treatments may tighten the gut through as yet unknown mechanisms.