Nowadays, radiotherapy has become an integral part of the treatment regimen in various malignancies for curative or palliative purposes. Ionizing radiation interacts with biological systems to produce free radicals, which attack various cellular components. Radioprotectors act as prophylactic agents that are administered to shield normal cells and tissues from the harmful effects of radiation. Melatonin has been shown to be both a direct free radical scavenger and an indirect antioxidant by stimulating antioxidant enzymes and suppressing prooxidative enzymes activity. In addition to its antioxidant property, there have also been reports implicating antiapoptotic function for melatonin in normal cells. Furthermore, through its antitumor and radiosensitizing properties, treatment with melatonin may prevent tumor progression. Therefore, addition of melatonin to radiation therapy could lower the damage inflicted to the normal tissue, leading to a more efficient tumor control by use of higher doses of irradiation during radiotherapy. Thus, it seems that, in the future, melatonin may improve the therapeutic gain in radiation oncology treatments.