Childhood obesity and metabolic syndrome (MetS) are multifactorial diseases influenced by genetic and environmental factors. The Mediterranean Diet (MD) seems to modulate the genetic predisposition to obesity or MetS in European adults. The FTO gene has also been shown to have an impact on the MD benefits to avoid obesity or MetS. Since these interaction effects have been scarcely analyzed in European youth, the aim was to describe the gene–MD interplay, analyzing the impact of the genetic factors to reduce the obesity and MetS risk through MD adherence, and the MD impact in the obesity and MetS genetic profile. From the limited evidence on gene–MD interaction studies in European youth, a study showed that the influence of high MD adherence on adiposity and MetS was only observed with a limited number of risk alleles; the gene–MD interplay showed sex-specific differences, being higher in females. Most results analyzed in European adults elucidate that, the relationship between MD adherence and both obesity and MetS risk, could be modulated by obesity genetic variants and vice versa. Further research is needed, to better understand the inter-individual differences in the association between MD and body composition, and the integration of omics and personalized nutrition considering MD.