The main goal of cancer chemoprevention is to prevent or halt the progression of carcinogenesis with the administration of synthetic or natural compounds. Fundamental chemopreventive strategies include inhibition of genetic damage, anti-proliferation/cell cycle regulation, and induction of apoptosis and anti-inflammatory processes, which may be critical for carcinogenesis intervention. Recently, a new paradigm for identifying chemopreventive agents has been implemented. It focuses on defining new biomarkers that can be used to evaluate chemopreventive efficacy based on multistage carcinogenesis. The functional roles of chemopreventive agents are associated with the modulation of nuclear factor kappa B, nuclear factor erythroid 2-related factor, p53, AMPK/mTOR, phosphatidylinositol 3-kinase, epidermal growth factor receptor, cyclooxygenase-2, chemokine (C-X-C motif) receptor 2, and sphingosine-1-phosphate. This paper summarizes the genetic and epigenetic effects of chemopreventive agents on the expression of cancer-related target genes mediated by epigenetic alterations, such as DNA methylation and histone modifications. This review will provide unique and effective strategies for reducing cancer and aging-related diseases in humans.