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Cancer represents a large group of diseases accounting for nearly 10 million deaths each year. Various treatment strategies, including surgical resection combined with chemotherapy, radiotherapy, and immunotherapy, have been applied for cancer treatment. However, the outcomes remain largely unsatisfying. Melatonin, as an endogenous hormone, is associated with the circadian rhythm moderation. Many physiological functions of melatonin besides sleep–wake cycle control have been identified, such as antioxidant, immunomodulation, and anti-inflammation. In recent years, an increasing number of studies have described the anticancer effects of melatonin. This has drawn our attention to the potential usage of melatonin for cancer treatment in the clinical setting, although huge obstacles still exist before its wide clinical administration is accepted. The exact mechanisms behind its anticancer effects remain unclear, and the specific characters impede its in vivo investigation. In this review, we will summarize the latest advances in melatonin studies, including its chemical properties, the possible mechanisms for its anticancer effects, and the ongoing clinical trials. Importantly, challenges for the clinical application of melatonin will be discussed, accompanied with our perspectives on its future development. Finally, obstacles and perspectives of using melatonin for cancer treatment will be proposed. The present article will provide a comprehensive foundation for applying melatonin as a preventive and therapeutic agent for cancer treatment. [ABSTRACT FROM AUTHOR]