Proton pump inhibitors (PPIs) are potent blockers of gastric acid secretion, and are widely regarded as the agents of choice for the treatment of acid-peptic disorders. For patients with upper gastrointestinal symptoms of uncertain etiology, improvement with PPI therapy is considered prima facie evidence of a pathogenetic role for acid-peptic disease. In addition to anti-secretory effects, however, PPIs have been found to have anti-oxidant properties and direct effects on neutrophils, monocytes, endothelial, and epithelial cells that might prevent inflammation. Those anti-inflammatory effects of the PPIs might influence a variety of inflammatory disorders, both peptic and non-peptic, within and outside of the gastrointestinal tract. The purpose of this report is to review the mechanisms whereby PPIs might exert anti-inflammatory effects exclusive of gastric acid inhibition, to discuss the clinical implications of those effects, and to emphasize that a clinical response to PPIs should not be construed as proof for an underlying acid-peptic disorder.