Whether theranostic testing to discern person-to-person and population differences in drug metabolism pathways offers clinical guidance in oncology for fluoropyrimidines such as 5-fluorouracil (5-FU) remains an open question. Extensive basic and clinical studies have been performed over the past several decades with regard to personalizing treatment with fluoropyrimidines, optimizing patients quality of life and reducing risks for severe and fatal toxic events. A variety of genetic variants in the dihydropyrimidine dehydrogenase (DPYD) gene were thus identified, and have been clustered according to their clinical and predictive value. However, further research is still needed as the DPYD gene is highly variable, complicating the attempts to establish genotype-phenotype correlations. Therefore, to individualise 5-FU therapy, several integrative/complementary approaches appear to be indicated to determine the dihydropyrimidine dehydrogenase metabolizer status. In principle, these diagnostic approaches in assessing dihydropyrimidine dehydrogenase activity include genotyping and phenotyping for the DPYD. This paper presents a critical summary and evaluation of the current state of research on both DPYD genotyping and phenotyping, and the pharmacogenetic syndrome of dihydropyrimidine dehydrogenase deficiency more generally. For DPYD based personalized medicine diagnostics to advance forward to become standard state of the art in routine testing, we also suggest the need for additional genetic, biological and clinical characterization of this pharmacologically significant variation across different global populations.