Leukemia or cancer of blood is a well-known cancer, which affects a range of people from newborns to the very old. It is a public health problem throughout the world. By way of treatment, due to the lack of specific anticancer therapies, common treatments of leukemia lead to severe side effects. Nonspecific anticancer drugs result in inhibition of normal cell growth and thereby their necrosis. Moreover, drug resistance is an additional problem, which stands in the way of leukemia treatment. Thus, finding new treatments for leukemia is essential. Melatonin, as a natural product, has been shown to be effective in a wide variety of diseases such as coronary heart disease, schizophrenia, chronic pain, and Alzheimer's disease. In addition, melatonin levels have been observed to be altered in different cancers, such as breast cancer, colorectal cancer endometrial cancer, and hematopoetical cancers. Anticancer features of melatonin such as pro-oxidation, apoptosis induction, antiangiogenesis property and metastasis and invasion inhibition suggest that this natural compound can be used as a potential agent in novel therapeutic strategies for cancers. Also, it has been reported that melatonin has positive and protective effects on different physiological reactions and in normal bone marrow cells suggesting effectiveness in leukemia therapy. Thus, the aim of our paper was to depict and summarize the main molecular targets of melatonin on leukemia models.