Gastric acid is pathogenic in many gastrointestinal disorders, such as gastroesophageal reflux disease and peptic ulcer disease. Proton pump inhibitors (PPIs) are the antisecretory drugs of choice for serious acid-related conditions. Ample recent data exist to explicate virtually every aspect of the clinical management of acid-peptic disorders with PPIs. Although all PPIs are effective, there are some differences in their clinical performance, particularly in terms of the degree and speed of gastric acid suppression. Rapid onset of acid suppression may be particularly relevant to newer approaches, such as 'on-demand' or intermittent therapy for non-erosive reflux disease and shorter regimens for Helicobacter pylori eradication. New data, in addition, highlight differences in PPI metabolism that may both affect efficacy and predispose patients to drug-drug interactions. PPI selection should involve the awareness of these issues.