Phenoconversion is a phenomenon that converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, thereby modifying their clinical response to that of genotypicPMs. Phenoconversion, usually resulting from nongenetic extrinsic factors, has a significant impact on the analysis and interpretation of genotype‐focused clinical outcome association studies and personalizing therapy in routine clinical practice. The high phenotypic variability or genotype–phenotype mismatch, frequently observed due to phenoconversion within the genotypicEMpopulation, means that the real number of phenotypicPMsubjects may be greater than predicted from their genotype alone, because many genotypicEMs would be phenotypicallyPMs. If the phenoconverted population with genotype–phenotype mismatch, most extensively studied forCYP2D6, is as large as the evidence suggests, there is a real risk that genotype‐focused association studies, typically correlating only the genotype with clinical outcomes, may miss clinically strong pharmacogenetic associations, thus compromising any potential for advancing the prospects of personalized medicine. This review focuses primarily on co‐medication‐induced phenoconversion and discusses potential approaches to rectify some of the current shortcomings. It advocates routine phenotyping of subjects in genotype‐focused association studies and proposes a new nomenclature to categorize study populations. Even with strong and reliable data associating patients' genotypes with clinical outcome(s), there are problems clinically in applying this knowledge into routine pharmacotherapy because of potential genotype–phenotype mismatch. Drug‐induced phenoconversion during routine clinical practice remains a major public health issue. Therefore, the principal challenges facing personalized medicine, which need to be addressed, include identification of the following factors: (i) drugs that are susceptible to phenoconversion; (ii) co‐medications that can cause phenoconversion; and (iii) dosage amendments that need to be applied during and following phenoconversion.