The term ‘antioxidant paradox’ is often used to refer to the observation that oxygen radicals and other reactive oxygen species are involved in several human diseases, but giving large doses of dietary antioxidant supplements to human subjects has, in most studies, demonstrated little or no preventative or therapeutic effect. Why should this be? First, the role of reactive oxygen species in the origin and/or progression of most human diseases is unclear, although they are probably important in cancer, neurodegenerative diseases and perhaps some others. Second, the endogenous antioxidant defences in the human body are complex, interlocking and carefully regulated. The body's ‘total antioxidant capacity’ seems unresponsive to high doses of dietary antioxidants, so that the amount of oxidative damage to key biomolecules is rarely changed. Indeed, manipulation of endogenous antioxidant levels (e.g. by supplying weak pro-oxidants) may be a more useful approach to treatment and prevention of diseases in which reactive oxygen species are important than is consumption of large doses of dietary antioxidants.