Cytochrome P450 2C19 (CYP2C19) is a key enzyme affecting the pharmacokinetics of many clinically important drugs. Individuals are classified as extensive metabolisers (EMs) or poor metabolisers (PMs) based on their ability to metabolise (S)-mephenytoin or other CYP2C19 substrates. Eight variant alleles (CYP2C19*2 to CYP2C19*8) predict PMs. The distribution of EM and PM genotypes and phenotypes varies widely among ethnic groups. Nongenetic factors such as enzyme inhibition, induction, old age, and liver cirrhosis can also modulate CYP2C19 activity. In EMs, about 80% of the doses of proton pump inhibitors (PPIs) like omeprazole, lansoprazole, and pantoprazole are cleared by CYP2C19, while CYP3A is more important in PMs. PMs experience higher drug exposure, leading to more effective acid suppression and better healing of ulcers. The pharmacoeconomic value of CYP2C19 genotyping is unclear, but it could save approximately $5000 per 100 Asians tested. Genotyping before PPI treatment for reflux disease and H. pylori infection is cost-effective for determining appropriate treatment duration and dosage. Phenytoin plasma concentrations and toxicity increase in patients with CYP2C19 inhibitors or variant alleles, suggesting the need for CYP2C19 and CYP2C9 genotyping to optimize phenytoin dosage. Tricyclic antidepressants may have increased toxicity in patients with reduced CYP2C19 and/or CYP2D6 activity. CYP2C19 is a major enzyme in proguanil activation, but there is no clinical evidence that PMs are at greater risk for malaria prophylaxis failure. Diazepam clearance is reduced in PMs or when CYP2C19 inhibitors are co-prescribed, but clinical consequences are generally minimal. Many studies have explored the relationship between CYP2C19 genotype and susceptibility to xenobiotic-induced disease, but none are compelling. The discovery of the first PM of mephenytoin at Vanderbilt University in 1979 and the genetic basis for this phenotype have spurred extensive research into CYP2C19's role in drug metabolism. Studies have confirmed that (S)-mephenytoin hydroxylase is CYP2C19. Research has identified seven alleles that predict PMs, with marked ethnic variation in PM frequency. CYP2C19 is involved in the metabolism of many frequently prescribed drugs, and reliable phenotyping and genotyping tools are available for screening.Cytochrome P450 2C19 (CYP2C19) is a key enzyme affecting the pharmacokinetics of many clinically important drugs. Individuals are classified as extensive metabolisers (EMs) or poor metabolisers (PMs) based on their ability to metabolise (S)-mephenytoin or other CYP2C19 substrates. Eight variant alleles (CYP2C19*2 to CYP2C19*8) predict PMs. The distribution of EM and PM genotypes and phenotypes varies widely among ethnic groups. Nongenetic factors such as enzyme inhibition, induction, old age, and liver cirrhosis can also modulate CYP2C19 activity. In EMs, about 80% of the doses of proton pump inhibitors (PPIs) like omeprazole, lansoprazole, and pantoprazole are cleared by CYP2C19, while CYP3A is more important in PMs. PMs experience higher drug exposure, leading to more effective acid suppression and better healing of ulcers. The pharmacoeconomic value of CYP2C19 genotyping is unclear, but it could save approximately $5000 per 100 Asians tested. Genotyping before PPI treatment for reflux disease and H. pylori infection is cost-effective for determining appropriate treatment duration and dosage. Phenytoin plasma concentrations and toxicity increase in patients with CYP2C19 inhibitors or variant alleles, suggesting the need for CYP2C19 and CYP2C9 genotyping to optimize phenytoin dosage. Tricyclic antidepressants may have increased toxicity in patients with reduced CYP2C19 and/or CYP2D6 activity. CYP2C19 is a major enzyme in proguanil activation, but there is no clinical evidence that PMs are at greater risk for malaria prophylaxis failure. Diazepam clearance is reduced in PMs or when CYP2C19 inhibitors are co-prescribed, but clinical consequences are generally minimal. Many studies have explored the relationship between CYP2C19 genotype and susceptibility to xenobiotic-induced disease, but none are compelling. The discovery of the first PM of mephenytoin at Vanderbilt University in 1979 and the genetic basis for this phenotype have spurred extensive research into CYP2C19's role in drug metabolism. Studies have confirmed that (S)-mephenytoin hydroxylase is CYP2C19. Research has identified seven alleles that predict PMs, with marked ethnic variation in PM frequency. CYP2C19 is involved in the metabolism of many frequently prescribed drugs, and reliable phenotyping and genotyping tools are available for screening.