Proton pump inhibitors represent an important advance in the treatment of acid-peptic disease. Omeprazole, the prototype of the drug class, produces a profound and sustained degree of gastric acid suppression. Recent studies confirm earlier reports that omeprazole 20 mg/d is generally more effective than standard histamine2 receptor antagonist (H2RA) dosage regimens in treating duodenal ulcer (DU), gastric ulcer (GU), and erosive esophagitis. Omeprazole tends to accelerate DU and GU healing, especially during the first 2 weeks of treatment, and also accelerates mucosal healing in patients with all grades of esophagitis. Omeprazole is the drug of choice for treating patients with large or refractory ulcers, severe or refractory erosive esophagitis, Barrett's esophagus, and Zollinger-Ellison syndrome. Maintenance therapy with omeprazole seems to reduce ulcer recurrence and esophagitis, but optimal treatment regimens must be established. Dual therapy with omeprazole and amoxicillin shows encouraging results in eradicating Helicobacter pylori, reducing duodenal ulcer recurrence rates, and altering the natural history of peptic ulcer disease. Further studies are required to determine the efficacy of omeprazole in preventing nonsteroidal anti-inflammatory drug-induced ulcers and stress-related mucosal bleeding, and in treating upper gastrointestinal bleeding. Omeprazole is well-tolerated in the majority of patients receiving either short-term or long-term treatment. The type and frequency of adverse effects are similar to those reported with the H2RAs. There is no evidence to support genotoxicity or hypergastrinemia-induced enterochromaffin-like cell carcinoid of the stomach in patients receiving omeprazole treatment for more than 5 years. Omeprazole interacts selectively with hepatic P-450 and may potentially interact with phenytoin, warfarin, or diazepam. Pharmacoeconomic studies suggest that treatment with omeprazole provides a significant cost-savings over the H2RAs in patients with moderate to severe erosive esophagitis and possibly in patients with DU. Lansoprazole, a newly developed proton pump inhibitor, seems to offer no clear advantage over omeprazole.