Proton pump inhibitors (PPIs) are widely used for the treatment of gastroesophageal reflux disease as well as other acid-related disorders. PPIs are metabolized primarily via the CYP2C19 and CYP3A4 isoenzymes; their activity is influenced both by exogenous and endogenous (pharmacogenetic) factors. The CYP2C19 polymorphism affects the metabolism of PPIs, causing large individual pharmacokinetic variations. Differences in the CYP2C19-mediated metabolism can produce marked interpatient variability in acid suppression, in drug-interaction potential and in clinical efficacy. Understanding the pharmacokinetic properties of PPIs and examining the pharmacogenetic alterations may help clinicians optimize PPI therapy and administer individual treatment, especially to nonresponder patients with gastroesophageal reflux disease or ulcer or after failed eradication therapy.