Given the widespread use of potent acid suppressive therapies and primary caregivers’ increasing comfort with prescribing these medications at high doses, the patient population presenting to gastroenterologists for symptoms of gastroesophageal reflux disease (GERD) has changed. Whereas previous consultation often revolved around the control of erosive disease and other mucosal manifestations of GERD, and terminated with the prescription of proton pump inhibitor (PPI) therapy, gastroenterologists often now only enter the scene after failure of PPI therapy, for symptoms either resistant or only partially responsive to these medications. Because of the high proportion of subjects with esophagitis who are healed with PPI, 1,2 upper endoscopy of such individuals is low yield, 3 with only a small minority demonstrating erosive disease. The care of such patients is challenging. High-quality evidence supporting useful diagnostic testing or alternative effective therapies is largely lacking. However, the number of subjects with GERD symptoms incompletely or nonresponsive to PPI therapies is high, and their utilization of healthcare resources is substantial. The purpose of this mini-review is to examine the definition and epidemiology of esophageal GERD symptoms incompletely responsive to PPI therapy, the potential pathophysiologic mechanisms behind these symptoms, the differential diagnosis and evaluation of such patients, and current and developing therapeutic options.