The broad-spectrum triazole antifungal agent voriconazole is highly efficacious against invasive fungal infections (IFIs) caused by Aspergillus spp. and Candida spp. IFIs are associated with high rates of mortality and morbidity, especially in vulnerable populations such as patients with hematopoietic stem cell transplant as well as other immunocompromised patients. Efficacy of voriconazole in these patients is critical to ensure positive outcomes and reduce mortality. However, a major limitation of voriconazole is the risk of adverse events such as hepatotoxicity and neurotoxicity. As such, therapeutic drug monitoring (TDM) has been suggested as a mechanism to optimize both efficacy and safety. The aim of this review was to summarize and evaluate evidence from the primary literature that assessed TDM outcomes for voriconazole as well as evaluate the association between CYP2C19 polymorphism and the clinical outcomes of voriconazole. Findings showed associations for both efficacy and safety outcomes with measurement of drug concentrations, yet exact targets or thresholds remain unclear. As such, TDM should be reserved for those patients not responding to therapy with voriconazole or those experiencing adverse drug reactions. Future studies should attempt to further define these populations within controlled settings. Studies that evaluated the effect of CYP2C19 genetic polymorphism on clinical outcomes found no significant relationship between CYP2C19 genotype and hepatotoxicity. These negative findings may be due to lack of power, use of phenotypes not well-defined, and the presence of other interacting factors that may impact voriconazole pharmacokinetics. Future well-designed studies are warranted to confirm these findings.