The dilemma whether supplementations of dietary antioxidants might prevent the adverse consequences of oxidative stress, the inadequacy of the analytical methods employed to quantify oxidant scavenging ability (OSA) levels in whole blood and the distribution and fate of polyphenols and their metabolites in various body compartments following oral consumption are discussed. While none-metabolized polyphenols might exert their antioxidant effects mainly in the oral cavity, metabolized polyphenols might be beneficial in the gastrointestinal tract to counteract the toxicity of oxidants and also of the sequelae of inflammatory processes. Although only micromolar amounts of polyphenols and their metabolites eventually reach the blood circulation, these may nevertheless still be highly effective as scavengers of reactive oxygen and nitrogen species because of their ability to synergize with plasma low molecular-weight antioxidants and with albumin. Polyphenols can avidly bind to surfaces of microorganisms and of blood cells to markedly enhance their OSA, therefore the routine quantifications of antioxidant levels conducted in clinical settings should always use catalase-rich whole blood but not as customary, plasma alone. In addition to their antioxidant and metal chelating properties, polyphenols may also act as signaling agents capable of affecting metabolic, inflammatory, autoimmune, carcinogenic and aging processes.