Among the many pathways dysregulated during the carcinogenic process, REGF seems to be one of the most promising pathways to target in order to achieve chemopreventive and anticancer effects. Indeed, chemoprevention, the use of natural or synthetic compounds in order to reverse, suppress or prevent the carcinogenic process, aims at the cellular level at regulating the growth and sensitivity to apoptosis of premalignant and malignant clones. REGF activation leads to uncontrolled cellular proliferation, resistance to apoptosis, angiogenesis and invasion. Furthermore, REGF is frequently overexpressed in many epithelial tumors. This review will focus on the rationale and the ongoing research areas related to chemopreventive approaches targeting REGF.