During the past two decades, enormous changes occurred in the management of gastric acid-related diseases. First, the histamine2-receptor antagonists were introduced, offering patients the first single-agent therapy that effectively reduced gastric acid secretion. Proton pump inhibitors became widely available in the early 1990s, and they generally appeared to be superior to the histamine2-receptor antagonists in acid-suppressing activity, symptom control and healing. Most physicians now use proton pump inhibitors as first-line treatment for many patients with acid-peptic disorders, including erosive gastro-oesophageal reflux disease (GERD), nonerosive reflux disease (NERD) and duodenal and gastric ulcers. Although proton pump inhibitors are often thought to be interchangeable, some differences have emerged in their pharmacological properties, which may be reflected in some aspects of clinical efficacy. Such differences include potency, speed of onset and duration of pH ‘holding times’. Helicobacter pylori has now been recognized as an important factor in the pathogenesis of acid-peptic disorders. It is clear that H. pylori eradication can dramatically reduce the chronicity of gastric and duodenal ulcers, and accepted therapeutic regimens for H. pylori eradication now include proton pump inhibitors and two or more antibiotics. Although all accepted proton pump inhibitor-based ‘triple therapies’ are roughly equivalent in efficacy, there is now a shortened regimen available that will potentially enhance compliance and decrease cost. This review examines the relative advantages of proton pump inhibitors vs. histamine2-receptor antagonists in the context of acid suppression and in various gastric acid-related diseases. A brief overview presents the pharmacodynamics and pharmacokinetics of the proton pump inhibitors with particular attention paid to rabeprazole, one of the newer drugs in its class.