Melatonin, the chief secretory product of the pineal gland, is a direct free radical scavenger, an indirect antioxidant, as well as an important immunomodulatory agent. In both in vitro and in vivo investigations, melatonin protected healthy cells from radiation-induced and chemotherapeutic drug-induced toxicity. Furthermore, several clinical studies have demonstrated the potential of melatonin, either alone or in combination with traditional therapy, to yield a favorable efficacy to toxicity ratio in the treatment of human cancers. This study reviews the literature from laboratory investigations that document the antioxidant and oncostatic actions of melatonin and summarizes the evidence regarding the potential use of melatonin in cancer treatment. This study also provides rationale for the design of larger translational research-based clinical trials.