Only about 50% of patients with non-erosive reflux disease (NERD) respond to standard doses of proton pump inhibitors (PPI). Various mechanisms have been proposed to explain PPI failure. Visceral hypersensitivity plays a basic role in the pathogenesis of NERD. Causes of persistent symptoms have been determined in 60% of patients with PPI-resistant NERD, including non-acid reflux (35-40%), acid reflux (10-15%), esophageal motility disorders (10%) and eosinophilic esophagitis (2%). Treatment based on these causes has been shown to improve patient symptoms. The causes of symptoms in the remaining 40% of patients, however, remain unknown, and these patients are often diagnosed with functional heartburn. Studies are needed to clarify the pathophysiologic mechanisms underlying functional heartburn in these patients.