There has been recent interest into the potential role of cellular and molecular mechanisms in the pathophysiology of irritable bowel syndrome (IBS). Although the intestinal mucosa of IBS patients is endoscopically and histologically "normal," it contains an increased number of activated T lymphocytes and mast cells, along with evidence of an increased release of mediators known to signal to epithelial, neuronal, and muscle cells leading to intestinal dysfunction. In this issue, Dunlop et al. provide evidence of increased intestinal permeability in patients with diarrhea predominant IBS. There is now consistent evidence indicating that mucosal barrier defects allow the passage of an increased load of luminal antigens of dietary and bacterial origin which, in turn, elicit the activation of mucosal immune responses involved in the generation of diarrhea. Further work has now to be done to better understand the interplay among luminal factors, epithelial cells, and mucosal immunocytes in the pathogenesis of IBS.