Gastroesophageal reflux disease (GERD) is a common disease that is often diagnosed based on typical symptoms of heartburn and regurgitation. In addition to these more classic manifestations, GERD is increasingly associated with extra-esophageal symptoms, including chronic cough, asthma, laryngitis, and dental erosions. Due to the poor sensitivity of endoscopy and pH monitoring, and the poor specificity of laryngoscopy, empiric therapy with proton pump inhibitors (PPIs) is now considered the initial diagnostic step in patients suspected of having GERD-related symptoms. For those who improve with PPIs, GERD is the presumed etiology, but for those who remain unresponsive to such therapy, further diagnostic testing with impedance/pH monitoring may be necessary in order to exclude refractory acid or weakly acid reflux. In those with normal test results despite PPI therapy and continued symptoms, causes other than GERD may be pursued. Recent data suggest that in patients with extra-esophageal symptoms, objective findings of moderate-sized hiatal hernia and moderate reflux on pH testing may predict response to acid suppressive therapy. PPI-unresponsive patients usually have causes other than GERD for their extra-esophageal symptoms and continued PPI therapy in this group is not recommended.