Purpose of the Review <p>This literature review provides examples of the influence of certain genetic variants on health outcomes after dietary polyphenol consumption or supplementation. Available evidence is organized according to the major classes of polyphenols (flavonoids, phenolic acids, stilbenes, lignans, and tannins) and their derived subgroups.</p> Recent Findings <p>Nutrigenetic studies have identified mainly single nucleotide polymorphisms located within genes involved in the biotransformation of phenolic acids, stilbenes, lignans and several flavonoid molecules. These genetic variants may affect polyphenol metabolism rates and related predisposition to chronic non-communicable diseases. Moreover, differential cardiometabolic outcomes upon polyphenol supplementation as dietary sources or nutraceuticals have been modulated by specific genotypes.</p> Summary <p>Although current evidence is still limited, growing gene-polyphenol interactions are contributing to systematically elucidate the biological functions of polyphenols; determine individual risk phenotypes to specific diseases or particular responses upon polyphenol exposure; and facilitate the prescription of personalized genotype-based doses of dietary polyphenols to optimize related health benefits. Additionally, the integration of genetics with other omics insights (epigenomics, transcriptomics, metagenomics, and metabolomics) trough biological systems and high-dimensional data analyses and interpretation may provide a more comprehensive understanding of polyphenol metabolism for precision nutrition applications in health and disease.</p>