Oxidative damage of cells and tissues is broadly implicated in human pathophysiology, including cardiometabolic diseases. Polyphenols, as important constituents of the human diet and potent in vitro free radical scavengers, have been extensively studied for their beneficial effects on cardiometabolic health. However, it has been demonstrated that the in vivo antioxidant activity of polyphenols is distinct from their in vitro free radical-scavenging capacity. Indeed, bioavailability of nutritional polyphenols is low and conditioned by complex mechanisms of absorption, distribution, metabolism and excretion. Nowadays, it is commonly accepted that the cellular antioxidant activity of polyphenols is mainly carried out via modification of transcription of genes involved in antioxidant defence. Importantly, polyphenols also contribute to cardiometabolic health by modulation of a plethora of cellular processes that are not directly associated with antioxidant enzymes, through nutri(epi)genomic mechanisms. Numerous human intervention studies have demonstrated beneficial effects of polyphenols on the key cardiometabolic risk factors. However, inconsistency of the results of some studies led to identification of the inter-individual variability in response to consumption of polyphenols. In perspective, a detailed investigation of the determinants of this inter-individual variability will potentially lead us towards personalised dietary recommendations. The phenomenon of inter-individual variability is also of relevance for supplementation with antioxidant (pro)vitamins.