Selenium (Se) is not yet conclusively classified as an essential nutrient required for plant growth. However, much attention has been devoted to its important role in human health since Se enrichment affects the production of primary and secondary metabolites. A strong link between low levels of Se and cancer and cardiac diseases has been proven. Thus, Se enrichment of crops has been established as a pioneering strategy to enhance Se intake by animals and humans. It has been proven that Se biofortification through a foliar application or in the growth medium has increased Se levels in plant tissues without loss of productivity or qualitative properties. However, to achieve the desirable level of Se and promote human health, Se accumulation in plants should be quantified and balanced because Se enrichment may affect their nutrient balance. This timely review provides a broad overview of the metabolic changes induced in plants by Se enrichment. Additionally, it highlights the contrasting effects of Se biofortification on the up-and-down-regulation of several secondary metabolites including phenolics, flavonoids, and their derivatives, as well as glucosinolates.