We have recently proposed a new paradigm for understanding how antioxidants in fruit and vegetables provide protective effects for health . Here we describe how this new paradigm is relevant to explaining how polyphenols in wine can provide health benefits. The new paradigm of “para-hormesis” is based on the reality that in cells, the by far major antioxidant mechanism is enzyme-catalyzed reduction of hydroperoxides rather than non-enzymatic scavenging of free radicals and other oxidants and that dietary antioxidants increase antioxidant enzymes and their substrates. Indeed, non-enzymatic scavenging by wine polyphenols may be restricted to the intestinal lumen as kinetic considerations rule out a significant contribution of non-enzymatic scavenging in cells. Indeed, antioxidants function through their metabolism in cells to electrophiles that induce antioxidant enzymes and elevate the concentrations of nucleophiles, particular NADPH, glutathione and thioredoxin that are the substrates for these enzymes. This maintenance of “nucleophilic tone” provides the means for “antioxidant defense”.