Epigenetic changes refer to modifications caused by heritable but potentially reversible changes in gene expression not coded in the DNA sequence. Evidence has been provided that various environmental factors and dietary bioactive compounds contribute to cancer development through epigenetic mechanisms. The main mechanisms of epigenetic control in mammals are DNA methylation, histone modifications, and RNA silencing through noncoding RNAs. The inhibition of DNA methyltransferases (DNMTs) involved in DNA methylation of CpG-rich regions of gene promoters and various enzymes involved in the chromatin condensation such as histone deacetylases (HDACs) have been recognized as potent strategies for cancer therapy and chemoprevention. Treatments using natural compounds such as green tea polyphenols, soy isoflavones, curcumin, resveratrol, isothiocyanates, and butyrate (an intestinal product from dietary fiber) modulate DNMT or HDAC gene expression and/or protein levels and activities, indicating that natural compounds could have strong potential to reverse epigenetic changes, without the adverse toxic effects associated with synthetic epigenetic inhibitors used in chemotherapy. Further characterization of the chemopreventive properties of various dietary bioactive compounds is warranted to potentially establish the clinical utility of dietary factors as anticancer compounds either alone or in combination with other dietary factors or clinically relevant therapeutics. Moreover, these characterizations are useful for personalized dietary recommendations and chemopreventive strategies for reducing cancer incidence.