Melatonin is a ubiquitous molecule on the phylogenetic scale, and cancer genes, inherent to the coexistence and cooperation between cells, appeared with multicellularity in ancestral metazoans. It is not surprising that the functional network of the indoleamine intersects with the malfunction of pathways responsible for cancer during evolution. Attention paid to melatonin over the past decades has revealed extraordinary pleiotropy involving the synchronization of endogenous rhythms, control of redox metabolism, receptor-mediated downstream signaling, and (epi)genetic regulation, among others. This multiplicity of actions outlines indoleamine as a protective agent that prevents both damage to cellular structures and the alteration of homeostasis. Instead, cancer represents the tectonic convulsion of cellular stabilization mechanisms to put them at the service of uncontrolled growth and propagation. From this perspective, it is clear that melatonin biochemistry is placed at the center of the cancer scene and, more importantly, that its functionalities can be potentially antagonistic. Research on the functional biology of melatonin has given rise to an important volume of epidemiological, in vitro, and animal studies that all together point directly and indirectly to its ability to inhibit critical carcinogenesis steps. However, there is still much basic and translational knowledge to be achieved, namely systematic research programs in animal models and clinical trials that would clarify the possibilities of melatonin in the prevention and treatment of the disease. Information continues to accumulate and ongoing research needs regular state-of-the-art updates. This chapter attempts to answer this concern by summarizing the latest findings on the mechanistic actions of melatonin in critical processes of tumor development. In addition, recent evidence on the therapeutic capacity of melatonin in the clinical setting of cancer patients is presented.