Proton pump inhibitors (PPIs) have become some of the most frequently prescribed medications for treatment of adults and children. Their effectiveness for treatment of peptic conditions in the pediatric population, including gastric ulcers, gastroesophageal reflux disease (GERD), and Helicobacter pylori infections has been established for children older than 1 year. Studies of the preverbal population of neonates and infants have identified doses that inhibit acid production, but the effectiveness of PPIs in the treatment of GERD has not been established except for the recent approval of esomeprazole treatment of erosive esophagitis in infants. Reasons that have been proposed for this are complex, ranging from GERD not occurring in this population to a lack of histologic identification of esophagitis related to GERD to questions about the validity of symptom scoring systems to identify esophagitis when it occurs in infants. The effectiveness of PPIs relates to their structures, which must undergo acidic activation within the parietal cell to allow the PPI to be ionized and form covalent disulfide bonds with cysteines of the H(+)-K(+)-adenosine triphosphatase (H(+)-K(+)-ATPase). Once the PPI binds to the proton pump, the pump is inactivated. Some PPIs, such as omeprazole and rabeprazole bind to cysteines that are exposed, and their binding can be reversed. After irreversible chemical inhibition of the proton pump, such as occurs with pantoprazole, the recovery of the protein of the pump has a half-life of around 50 h. Cytochrome P450 (CYP) 2C19 and to a lesser degree CYP3A4 clear the PPIs metabolically. These enzymes are immature at birth and reach adult levels of activity by 5-6 months after birth. This parallels studies of the maturation of CYP2C19 to adult levels by roughly the same age after birth. Specific single nucleotide polymorphisms of CYP2C19 reduce clearance proportionally and increase exposure and prolong proton pump inhibition. Prolonged treatment of pediatric patients with PPIs has not caused cancer or significant abnormalities.