Patients with refractory gastroesophageal reflux disease (GERD) are those who have persistent symptoms while being treated with proton pump inhibitors (PPIs). One third of GERD patients requiring a daily PPI are estimated to eventually experience treatment failure. These patients are usually referred for further investigation to confirm the presence of GERD or to identify other entities as the cause of symptoms. Tools that can be used in this diagnostic process include upper gastrointestinal endoscopy with analysis of esophageal biopsies, esophageal pH monitoring, impedance-pH monitoring, and esophageal bilirubin monitoring. The conventional diagnostic approach includes upper gastrointestinal endoscopy and ambulatory pH monitoring while receiving PPI therapy. New diagnostic techniques that may be useful with refractory GERD include impedance-pH monitoring, which is very sensitive in detecting persistent weakly acidic reflux, and bilirubin monitoring, which detects increased esophageal exposure to bile. Gastric pH monitoring should be reserved for patients in whom PPI resistance is suspected.