INTRODUCTION: Management of gastroesophageal reflux disease (GERD) is based on the concept that gastric contents, principally acid and pepsin, are responsible for symptoms of reflux and esophageal injury. Pharmacologic treatment is based on the principle that controlling intragastric pH will affect esophageal healing and subsequently symptom relief. RESULTS AND DISCUSSION: Control of pH can be accomplished with antisecretory agents, principally proton pump inhibitors (PPIs). The majority of patients respond to a single daily dose of a PPI; however, some will require higher doses, and a small percentage are "refractory" to twice daily dosing of these drugs. The success of these agents, and in fact the reasons for "failure," is elucidated by understanding the mechanism of action of PPIs and the effect of dose timing and meals on their efficacy. CONCLUSION: Awareness of new concerns regarding potential side effects of PPIs when used long-term require careful thought as GERD is a chronic disease with most needing some form of medical treatment over time. This article reviews the pharmacologic properties of PPIs and the impact on the treatment of GERD.