Since their introduction into clinical practice in the 1980s, proton pump inhibitors (PPIs) have proved to be of enormous value in the management of acid peptic disorders. They have become the treatment of choice for most, if not all, acid-related gastrointestinal disorders, including gastroesophageal reflux disease, peptic ulcer, and Zollinger-Ellison syndrome. With approval of an intravenous formulation, the benefits of PPIs are extended to critically ill patients for whom oral drug administration is often unsuitable. Five PPIs are approved for clinical use in the United States. Although they share a common core structure and mechanism of action, it is important to understand the general pharmacology of these agents and how they differ from histamine 2-receptor antagonists in order to optimize PPI therapy.