The aim of this article was to perform a systematic review on the role of melatonin in the prevention of cancer tumorigenesis--in vivo and in vitro--as well as in the management of cancer correlates, such as sleep-wake and mood disturbances. The International Agency for Research on Cancer recently classified "shift-work that involves circadian disruption" as "probably carcinogenic to humans" (Group 2A) based on "limited evidence in humans for the carcinogenicity of shift-work that involves night-work", and "sufficient evidence in experimental animals for the carcinogenicity of light during the daily dark period (biological night)". The clinical implications and the potential uses of melatonin in terms of biologic clock influence (e.g. sleep and mood), immune function, cancer initiation and growth, as well as the correlation between melatonin levels and cancer risk, are hereinafter recorded and summarized. Additionally, this paper includes a description of the newly discovered effects that melatonin has on the management of sleep-wake and mood disturbances as well as with regard to cancer patients' life quality. In cancer patients depression and insomnia are frequent and serious comorbid conditions which definitely require a special attention. The data presented in this review encourage the performance of new clinical trials to investigate the possible use of melatonin in cancer patients suffering from sleep-wake and mood disturbances, also considering that melatonin registered a low toxicity in cancer patients.