Despite significant research progress on the pathogenesis, molecular biology, diagnosis, treatment, and prevention of cancer its morbidity and mortality is still high around the world. The emerging resistance of cancer cells to anticancer drugs remains still a significant problem in oncology today. Furthermore, an important challenge is the inability of anticancer drugs to selectively target tumor cells thus sparing healthy cells. One of new potential options for efficient and safe therapy can be provided by opioid growth factor (OGF), chemically termed Met-enkephalin. It is an endogenous pentapeptide (Tyr-Gly-Gly-Phe-Met) with antitumor, analgesic and immune-boosting properties. Clinical trials have demonstrated that OGF therapy alone, as well as in combination with standard chemotherapies, is a safe, non-toxic anticancer agent that reduces tumor size. In this paper, we review the structure-activity relationship of OGF and its analogues. We highlight also OGF derivatives with analgesic, immunomodulatory activity and the ability to penetrate the blood-brain barrier and may be used as a safe agents enhancing chemotherapy efficacy and improving quality of life in cancer patients. The reviewed papers indicate that Met-enkephalin, as well as its analogues are interesting candidates for the development of novel, non-toxic and endowed with an analgesic activity anticancer drugs. More preclinical and clinical studies are needed to explore these opportunities.Copyright© Bentham Science Publishers; For any queries, please email at email@example.com.