Cytochrome P450 2C19 (CYP2C19) is a key enzyme responsible for the pharmacokinetics of several clinically important drugs. Individuals can be classified as extensive metabolizers (EMs) or poor metabolizers (PMs) based on their ability to metabolize (S)-mephenytoin or other CYP2C19 substrates. Eight variant alleles have been identified, with PMs being more prevalent in certain ethnic groups. Non-genetic factors like enzyme inhibition and induction, age, and liver cirrhosis also influence CYP2C19 activity. In EMs, proton pump inhibitors (PPIs) such as omeprazole, lansoprazole, and pantoprazole are primarily metabolized by CYP2C19, while CYP3A is more significant in PMs. PMs experience higher exposure to these drugs, leading to more effective acid suppression and better healing of ulcers. The cost-effectiveness of CYP2C19 genotyping for PPIs is unclear, but it may save costs for Asian patients. Genotyping can help determine appropriate treatment duration and dosages. Phenytoin plasma concentrations and toxicity increase in patients with CYP2C19 variants or inhibitors. Tricyclic antidepressant toxicity may also be increased in patients with diminished CYP2C19 and/or CYP2D6 activities. Proguanil activation to cycloguanil is a major role of CYP2C19, but PMs are not at higher risk for malaria failure. Diazepam clearance is reduced in PMs or when CYP2C19 inhibitors are prescribed, but the clinical impact is minimal. Research on the relationship between CYP2C19 genotype and susceptibility to xenobiotic-induced diseases has not yielded compelling results. The discovery of the first PM of mephentoin in 1979 and subsequent genetic studies have led to extensive research on CYP2C19 polymorphisms and their impact on drug metabolism. Reliable phenotyping and genotyping tools are available for screening CYP2C19 activity.Cytochrome P450 2C19 (CYP2C19) is a key enzyme responsible for the pharmacokinetics of several clinically important drugs. Individuals can be classified as extensive metabolizers (EMs) or poor metabolizers (PMs) based on their ability to metabolize (S)-mephenytoin or other CYP2C19 substrates. Eight variant alleles have been identified, with PMs being more prevalent in certain ethnic groups. Non-genetic factors like enzyme inhibition and induction, age, and liver cirrhosis also influence CYP2C19 activity. In EMs, proton pump inhibitors (PPIs) such as omeprazole, lansoprazole, and pantoprazole are primarily metabolized by CYP2C19, while CYP3A is more significant in PMs. PMs experience higher exposure to these drugs, leading to more effective acid suppression and better healing of ulcers. The cost-effectiveness of CYP2C19 genotyping for PPIs is unclear, but it may save costs for Asian patients. Genotyping can help determine appropriate treatment duration and dosages. Phenytoin plasma concentrations and toxicity increase in patients with CYP2C19 variants or inhibitors. Tricyclic antidepressant toxicity may also be increased in patients with diminished CYP2C19 and/or CYP2D6 activities. Proguanil activation to cycloguanil is a major role of CYP2C19, but PMs are not at higher risk for malaria failure. Diazepam clearance is reduced in PMs or when CYP2C19 inhibitors are prescribed, but the clinical impact is minimal. Research on the relationship between CYP2C19 genotype and susceptibility to xenobiotic-induced diseases has not yielded compelling results. The discovery of the first PM of mephentoin in 1979 and subsequent genetic studies have led to extensive research on CYP2C19 polymorphisms and their impact on drug metabolism. Reliable phenotyping and genotyping tools are available for screening CYP2C19 activity.