Differences are emerging with respect to the mode of metabolism of proton pump inhibitors. All, except rabeprazole, are metabolised primarily by the hepatic cytochrome P450 enzyme system, and common genetic polymorphisms of the CYP 2C19 iso-enzyme affect their clearance and bio-availability. This has been demonstrated to lead to inconsistency in terms of acid suppression across the CYP 2C19 genotypes for all proton pump inhibitors except for rabeprazole. Omeprazole and, more markedly, esomeprazole, differ from the other proton pump inhibitors in that their bio-availability increases over the first week of treatment. This is due to a progressive reduction in their hepatic clearance with repeat dosing. This reduced hepatic clearance appears to be due to the S-enantiomer of omeprazole-esomeprazole impairing the activity of hepatic CYP 2C19. The clinical significance of these differences in metabolism of the various proton pump inhibitors, and the possible benefits of the non-enzymatic metabolism of rabeprazole, require further investigation.