The role of acid, weak/nonacid, and bile in the genesis of esophageal mucosal damage and reflux symptoms is complex. Acid combined with pepsin and unconjugated bile acids are critical to the development of esophagitis and Barrett's esophagus. Acid alone may be the principal factor in determining the severity of esophagitis. Weak acid or nonacid reflux does not cause esophageal damage or damage to adjacent organs, such as the larynx or lungs. The primary cause of heartburn and regurgitation is acid reflux, but a minority of symptoms (5%-15%) can be triggered by weak acid or bile reflux. The role is changed among patients on proton pump inhibitors with persistent symptoms, where the majority of symptoms are now due to weak acid or bile reflux. The proximal extent of the reflux, regardless of its acidity, seems to be the key to reflux symptoms.