Proton pump inhibitors (PPIs) are widely prescribed for the treatment of gastro-oesophageal reflux disease (GORD) as well as gastric and duodenal ulcers, and these agents are now considered the drugs of choice for managing such acid-related disorders. Despite their well-documented efficacy and safety, first-generation PPIs (omeprazole, pantoprazole and lansoprazole) have notable limitations. These drugs exhibit substantial interpatient variability in pharmacokinetics and may have significant interactions with other drugs. The time of dosing and ingestion of meals may also influence the pharmacokinetics of these agents as well as their ability to suppress gastric acid secretion. First-generation PPIs also have a relatively slow onset of pharmacological action and may require several doses to achieve maximum acid suppression and symptom relief, possibly limiting their usefulness in on-demand GORD therapy. First-generation PPIs may also fail to provide 24-h suppression of gastric acid, and noctural acid breakthrough can occur even with twice-daily dosing. Both first- and second-generation PPIs may be associated with adverse events consequent to gastric acid suppression, but newer PPIs have the potential to overcome some critical pharmacokinetic, pharmacodynamic, and clinical limitations of the first-generation drugs.