Proton pump inhibitors (PPIs) have revolutionised the treatment of acid-related disorders, and they have also made it possible to define the spectrum of acid inhibition required for optimal treatment in each disorder. Five PPIs are now available: the older drugs, omeprazole, lansoprazole and pantoprazole, and the two newest, rabeprazole and esomeprazole. These agents have predominantly been developed in the younger adult population, and data for the elderly population are limited. Subtle differences have emerged between the old and the new PPIs in their pharmacokinetic, pharmacodynamic and efficacy profiles. The degree of clinical relevance of these differences in the adult population is in question. However, according to this review, based on the available data for the elderly and by inference from the adult population, the differences are highly relevant in the elderly population. Studies of the pharmacokinetics of older PPIs demonstrated considerable variation in drug clearance that was reflected in a wide range of efficacy related to acid suppression with standard dosages. The newer PPIs offer several advantages over older agents, particularly in terms of rapid, profound and consistent acid inhibition. Consistent acid inhibition is particularly important in the elderly since clinical response is often difficult to judge in this patient group. An individual's cytochrome P450 (CYP) 2C19 genotype predicts the degree of acid suppression and consequently the clinical efficacy of the PPIs. The older PPIs are predominantly metabolised by CYP2C19, with this being of more importance for omeprazole and lansoprazole than pantoprazole. The hepatic metabolism of rabeprazole is predominantly by nonenzymatic reactions and minimally by CYP-mediated reactions, which therefore confers an advantage over older PPIs in that genetic polymorphisms for CYP2C19 do not significantly influence rabeprazole clearance, clinical efficacy or potential for drug interactions. The metabolism of esomeprazole involves CYP2C19 but to a lesser extent than its predecessor omeprazole. Furthermore, esomeprazole has a more rapid onset of action and less variation in clearance rates than omeprazole. Drug clearance decreases with age independently of CYP2C19 status, exaggerating some of the differences between the PPIs and increasing the risk of drug interactions.