Proton pump inhibitors (PPIs) are targeted to the gastric acid pump, H+, K(+)-adenosine triphosphatase (ATPase). The drugs accumulate in the acid space of the parietal cell and convert to active sulfenamide by an acid-catalyzed reaction. Consequent covalent inhibition of H+, K(+)-ATPase blocks the final step of acid secretion, hence the PPIs omeprazole, lansoprazole, and pantoprazole are more effective than histamine2-receptor antagonists (H2RAs) in controlling acid secretion. Preclinical short- and long-term clinical surveillance data show these drugs to be well tolerated and safe. The PPIs heal the lesions of gastroesophageal reflux disease and lessen symptoms more effectively and more quickly than the H2RAs, and are effective and faster acting for peptic ulcer disease. Helicobacter pylori is causally implicated in the majority of peptic ulcers and in atrophic gastritis. Since PPIs, but not H2RAs, are synergistic with antibiotics in eradicating H. pylori, their use is appropriate in all acid-related diseases since all patients who are H. pylori positive require eradication as well as healing.