In the past decade, extensive studies have demonstrated that a wide spectrum of human diseases is a function of epigenome modulation. Environmental factors and lifestyle, particularly nutrition, can modify the regulation of the epigenome. Bioactive peptides (BAPs) derived from different sources (e.g., animal, vegetal and exogenous) can affect the epigenome through changes in DNA methylation, histone acetylation, non-coding RNAs, and miRNAs. Bioactive-derived food peptides with epigenetic effects can be a contributing factor in different medical conditions such as cancer, cardiovascular diseases (CVDs), neurological and neurodegenerative disorders, chronic obstructive pulmonary diseases (COPDs), and type 2 diabetes mellitus (T2DM). In this chapter, we have reviewed the role of bioactive food peptides in the prevention and treatment of chronic diseases through modulation of the epigenome. In particular, bioactive food peptides lunasin, BCM7(Beta-casomorphin-7), and GM7 (Gliadinomorphin-7) are shown to modify the epigenome and are used for the treatment of chronic diseases such as cancer, neurological and neurodegenerative disorders. Although only a few epigenetic drugs have currently been approved by the FDA, it is expected that bioactive food peptides with epigenetic effects will be a major category of approved drugs for the prevention and treatment of chronic diseases in the near future.