Pharmacotherapy – Since its approval by the United States Food and Drug Administration in 2002, voriconazole has become a key component in the successful treatment of many invasive fungal infections, including the most common, aspergillosis and candidiasis. Despite voriconazole’s widespread use, optimizing its treatment in an individual can be challenging due to significant interpatient variability in plasma concentrations of the drug. Variability is due to nonlinear pharmacokinetics and the influence of patient characteristics such as age, sex, weight, liver disease, and genetic polymorphisms in the cytochrome P450 2C19 gene (CYP2C19) encoding for the CYP2C19 enzyme, the primary enzyme responsible for metabolism of voriconazole. CYP2C19 polymorphisms account for the largest portion of variability in voriconazole exposure, posing significant difficulty to clinicians in targeting therapeutic concentrations. In this review, we discuss the role of CYP2C19 polymorphisms and their influence on voriconazole’s pharmacokinetics, adverse effects, and clinical efficacy.