Proton pump inhibitors (PPIs) are highly effective agents for the treatment of gastric acid-related disorders. They are metabolized by the cytochrome P450 (CYP) system, mainly via the enzyme CYP2C19. A genetically determined defect in this pathway results in impaired metabolism of PPIs, giving rise to three distinct phenotypes: rapid extensive (fast), extensive (medium), and poor (slow) metabolizers. These genetic mutations are more common in certain races, and there is, therefore, considerable inter-individual and -ethnic variation in the capacity to metabolize PPIs. The incidence of mutant alleles in a population treated for acid-related disorders may influence the efficacy of the treatment, with clinical implications for the prescribers of PPIs. Therapeutic failure, such as lack of symptom relief, or ineffective Helicobacter pylori eradication, can occur in rapid metabolizers who will have less available drug at a given dose. Conversely, poor metabolizers may be at risk of over-treatment, with increased incidence of adverse effects and unnecessary financial burden. Approaches to this problem include phenotyping or, preferably, genotyping patients prior to treatment with PPIs. This will allow tailoring dose regimens to the individual's metabolic capacity. An alternative strategy is the development of drugs that are either metabolized by genotype-independent pathways or are less susceptible to inter-individual genetic variation. Non-racemic PPIs fall into the latter category, and the first such agent, esomeprazole, is now commercially available.