Transient lower esophageal sphincter relaxations (TLESRs) are neurally mediated abrupt reductions in lower esophageal sphincter (LES) pressure. TLESRs are not usually associated with deglutition or secondary peristalsis but are thought to be necessary for venting swallowed air from the stomach. Their central role in acid reflux, however, makes them a compelling therapeutic target for patients with gastroesophageal reflux disease. Pharmacologic approaches for reducing TLESR frequency are being studied, but theoretically more promising are endoscopic approaches that interfere with mechanoreceptor function. Further study into the mechanisms of action of these approaches is needed, as are controlled clinical trials to define the true utility of these techniques and identify patients who will receive the most benefit.