The role of acid is very well established in the pathogenesis of gastroesophageal reflux disease (GERD). In the current era of frequent use of proton pump inhibitors, we are seeing increasing numbers of patients with symptoms that are refractory to acid suppression. Recent studies suggest that in patients being treated with proton pump inhibitors, non-acid reflux (composed of buffered gastric contents), esophageal hypersensitivity, esophageal motor dysfunction and psychological comorbidity can cause persistent symptoms. Concepts surrounding possible pathogenetic mechanisms leading to heartburn as a result of nonacid reflux and other mechanisms are explored, and potential treatments for this type of reflux are outlined in this review.