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Since several decades anti-oxidants have been much studied, and scientists have tried to prove the preventive and curative effects in many chronic diseases. However, it is not uncommon to find highly contradictory clinical results, which may explain that consumers are less enthusiastic for anti-oxidants food supplements. First of all, definitions should be reviewed, such as that of free radicals (FR); all of them are not toxic. Some of them, such as nitric oxide, are necessary for the proper physiological functioning of the body, and eliminating them would be a mistake! However, other reactive oxygen species (ROS), which are not FR, are toxic, such as hydrogen peroxide. We have also redefined the oxidative stress, which it is not only the result of an imbalance between oxidants and anti-oxidants, but also the consequence of imbalance in the cellular redox status. The mechanisms of action, bioavailability, synergy and methods to determine the level of anti-oxidants are very sensitive topics, and it is crucial to study them if we want to obtain reliable clinical studies. Given the failure of clinical studies about anti-oxidant, we try to explain strategies which should be followed. First of all, the nature of the anti-oxidant is important; and an anti-oxidant from a natural origin must be preferred. Then, we proposed that the dose-effect was certainly responsible for the failure of tests. Indeed, doses administered in the studies was either too weak to obtain significant results, or too high, becoming pro-oxidative and eliminating the basal concentration of ROS (physiological role). Involvement of mitochondria and glycation are particularly discussed. Nutrigenomics and nutrigenetics are also discussed, which study the interactions between genetics and nutrition. Genetic polymorphism can explain the variable absorption of micronutrients. This concept leads to a truth believed by all scientists, namely the need to provide the right anti-oxidant, in adequate quantity, at the right place, at the right time and for a particular individual. To increase the anti-oxidant capacity of the body, the exogenous intake of anti-oxidants must be increased or the endogenous synthesis of anti-oxidants (SOD, GPX, GSH) must be stimulated. Targeting mitochondria and increasing their overall anti-oxidant defence system will be a challenge. Increasing the bioavailability of anti-oxidants and studying their passage through the blood-brain barrier must be also taken in consideration.