CYP2D6 contributes to the metabolism of approximately 20-25% of drugs. However, CYP2D6 is highly polymorphic and different alleles can lead to impacts ranging from null to increase in activity. Moreover, there are commonly used drugs that potently inhibit the CYP2D6, thus causing 'phenoconversion' which can convert the genotypic normal metabolizer into phenotypic poor metabolizer. Despite growing literature on the clinical implications of non-normal CYP2D6 genotype and phenoconversion on patient-related outcomes, implementation of CYP2D6 pharmacogenetics and phenoconversion to guide prescribing is rare. This review focuses on providing the clinical importance of CYP2D6 pharmacogenetics and phenoconversion in precision medicine and summarizes the challenges and approaches to implement these into clinical practice.A literature search was performed using PubMed and clinical studies documenting the effects of CYP2D6 genotypes and/or CYP2D6 inhibitors on pharmacokinetics, pharmacodynamics or treatment outcomes of CYP2D6-metabolized drugs, and studies on implementation challenges and approaches.Considering the extent and impact of genetic polymorphisms of CYP2D6, phenoconversion by the comedications, and contribution of CYP2D6 in drug metabolism, CYP2D6 pharmacogenetics is essential to ensure drug safety and efficacy. Utilization of proper guidelines incorporating both CYP2D6 pharmacogenetics and phenoconversion in clinical care assists in optimizing drug therapy.