Suspected reflux symptoms that are refractory to proton pump inhibitors (PPIs) are rapidly becoming the most common presentation of gastroesophageal reflux disease (GERD) in patients seen in gastroenterology clinics. These patients are a heterogeneous group, differing in symptom frequency and severity, PPI dosing regimens, and responses to therapy (from partial to absent). Before testing, the physician needs to question the patient carefully about PPI compliance and the timing of drug intake in relation to meals. Switching PPIs or doubling the dose is the next step, but only 20% to 25% of the group refractory to PPIs will respond. The first diagnostic test should be upper gastrointestinal endoscopy. In more than 90% of cases, the results will be normal, but persistent esophagitis may suggest pill esophagitis, eosinophilic esophagitis, or rarer diseases, such as lichen planus, Zollinger-Ellison syndrome, or genotype variants of PPI metabolism. If the endoscopy results are normal, esophageal manometry and especially reflux testing should follow. Whether patients should be tested on or off PPI therapy is controversial. Most physicians prefer to test patients off PPIs to identify whether abnormal acid reflux is even present; if it is not, PPIs can be stopped and other diagnoses sought. Testing patients on PPI therapy allows nonacid reflux to be identified, but more than 50% of patients have a normal test result, leaving the clinician with a conundrum-whether to stop PPIs or continue them because the GERD is being treated adequately. Alternative diagnoses in patients with refractory GERD and normal reflux testing include achalasia, eosinophilic esophagitis, gastroparesis, rumination, and aerophagia. However, more than 50% will be given the diagnosis of functional heartburn, a visceral hypersensitivity syndrome. Treating patients with PPI-refractory GERD-like symptoms can be difficult and frustrating. Any of the following may help: a histamine-2 receptor antagonist at night, baclofen to decrease transient lower esophageal sphincter relaxations, pain modulators, acupuncture, or hypnotherapy. At this time, antireflux surgery should be limited to patients with abnormal acid reflux defined by pH testing and a good correlation of symptoms with acid reflux.