PPIs inhibit acid secretion by blocking Na+,K+-ATPase, aptly known as the “proton pump,” or the final common pathway of parietal cell acid secretion. PPIs are accepted as superior antisecretory agents to H2RAs for two reasons; first they are able to maintain intragastric pH at or above 4 for longer periods, and second, because of their unique ability to inhibit meal-induced acid secretion. PPIs can be used with excellent acid suppressive effects for indefinite periods and are not associated with tachyphylaxis. Drawbacks to PPI use in children include side effects of headache, diarrhea, constipation, and nausea seen in up to 14% of children. PPIs have not been approved for use in North America in infants. In addition, PPI use and resulting gastric achlorhydria in adults and in small cohorts of children retrospective studies have demonstrated an association with an increased incidence of community-acquired infections, alteration in intestinal bacterial flora, and deficiencies of vitamin B12. Nevertheless, the number of PPI prescriptions written for infants continues to increase. Accordingly, the 2009 Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of NASPGHAN and ESPGHAN state that risks of PPI therapy in infants may outweigh perceived benefits, which have not been substantiated by placebo-controlled trials.