Aerobic organisms need antioxidant defense systems to deal with free radicals which either are produced during aerobic respiration or may have an external origin. Oxidative stress, which is resulted from an imbalance between the production of free radicals and the ability of antioxidant defense mechanism to deactivate them, is involved in the development of many chronic diseases such as cancer, diabetes, cardiovascular diseases, and some neurodegenerative diseases. Reinforcing the antioxidant potential of the body has been considered as a strategy which could prevent and manage such conditions. In the previous review article published by British Journal of Nutrition, in 2014, for the first time, we concluded that riboflavin could alleviate oxidative stress. Although riboflavin can serve as a prooxidant when exposed to ultraviolet irradiation, the literature is replete with studies that support its antioxidant properties. Furthermore, recent evidence suggest that riboflavin may have a therapeutic potential in many conditions in which oxidative stress is involved, although, the therapeutic efficacy of riboflavin as an antioxidant requires further study under conditions of wellness and clinical disease.