For several decades, many antioxidants studies have emphasized the marked disparity between the beneficial effect of the antioxidants shown in preclinical studies and their inability to show beneficial effects in clinical trials. Besides, it is not uncommon to find highly contradictory clinical results, which may explain why consumers are less enthusiastic for antioxidant uses. This perspective article aims to highlights the critical role of Reactive Oxygen Species (ROS) and antioxidants, the potential mechanisms that might account for these discrepancies in clinical trials and some strategies to target oxidative stress and mitochondria by antioxidants. We need urgently to set up standard methods to evaluate antioxidants and oxidative stress in human and in particular at mitochondria level. The determination of what the basal level of ROS is in normal human may be used to identify pathologic ROS levels in patients and ultimately guide antioxidants treatment.