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Proton pump inhibitors (PPIs) are among the most widely used of prescription drugs. They have revolutionized the management of gastroesophageal reflux disease and other acid-related disorders. Although generally safe, concerns about possible adverse effects continue to arise. Some of these, such as gastric neoplasms, are of theoretical concern only and are related to suppression of gastric acid secretion and consequent hypergastrinemia; these have not been encountered in clinical practice despite millions of patient-years of use. Others are more idiosyncratic, unpredictable, and rare. In general, the therapeutic benefits of PPIs outweigh these potential risks. However, it is important that PPIs are only given for appropriate indications and that, whenever possible, they are used in the lowest effective dose. At present, there is no need for specific monitoring for adverse events during PPI therapy.