All the epithelia lining the gastrointestinal (GI) tract, including that of the esophagus, exhibit a transmucosal electrical potential difference (PD). The luminal surface of the GI mucosa is indeed electrically negative when compared with the serosal one. Although it was initially felt that the body of the esophagus exhibits a PD near 0 or slightly positive, recent studies, using parenteral reference electrodes, have shown a negative PD of around -15 mV. Measurement of esophageal PD has been mainly used to locate both the lower and the upper esophageal sphincters but very rarely to evaluate esophageal mucosal integrity in clinical settings, most probably due to the difficulties encountered during measurement of mucosal PD. Reliable techniques to measure esophageal PD simultaneously with esophageal pressure or mucosal pH are now available. Application of these recently developed methodologies showed that measurement of esophageal PD during either manometry or endoscopy provides meaningful information about mucosal integrity. Indeed, tissue injury, either neoplastic of inflammatory, usually results in a less negative PD. In contrast, an abnormally high negative PD is very often observed in patients with columnar-lined lower esophagus. In patients with microscopic reflux esophagitis, PD exhibits less negative values which are significantly correlated with the degree of the mucosal damage. Normalization of the altered PD after either medical or surgical treatment makes it an additional parameter to evaluate the effect of a given therapy.