Gastroesophageal reflux disease, especially when refractory to standard therapy, remains a significant clinical problem. Although symptom pathogenesis in erosive reflux disease is relatively easy to understand, it is less clear how exposure of the macroscopically normal mucosa in nonerosive reflux disease (NERD) is able to cause heartburn. Over recent years it has become apparent that there may be microscopic and functional defects in the esophageal epithelial barrier in NERD, a so-called impairment of esophageal mucosal integrity. This can be expressed in morphologic or in functional terms. Morphologically the epithelium in NERD displays dilated intercellular spaces, which may represent a failed epithelial barrier, probably due to disruption of cell apical junctional complexes. Functionally, the mucosa in NERD displays more permeability to ions and small molecules than that of control subjects. Both morphologic and functional changes can be induced by exposure to refluxate-like solutions in vitro and in vivo. This article summarizes the evidence for impairment of esophageal mucosal integrity, and discusses its possible role in disease pathogenesis.