Epigenetic regulatory mechanisms, encompassing diverse molecular processes including DNA methylation, histone post-translational modifications, and noncoding RNAs, are essential to numerous processes such as cell differentiation, growth and development, environmental adaptation, aging, and disease states. In many cases, epigenetic changes occur in response to environmental cues and lifestyle factors, resulting in persistent changes in gene expression that affect vascular disease risk during the lifetime of the individual. Biological aging—a powerful cardiovascular risk factor—is partly genetically determined yet strongly influenced by traditional risk factors, reflecting epigenetic modulation. Quantification of specific DNA methylation patterns may serve as an accurate predictor of biological age—a concept known as the epigenetic clock, which could help to refine cardiovascular risk assessment. Epigenetic reprogramming of monocytes rewires cellular immune signaling and induces a metabolic shift toward aerobic glycolysis, thereby increasing innate immune responses. This form of trained epigenetic memory can be maladaptive, thus augmenting vascular inflammation. Somatic mutations in epigenetic regulatory enzymes lead to clonal hematopoiesis of indeterminate potential, a precursor of hematologic malignancies and a recently recognized cardiovascular risk factor; moreover, epigenetic regulators are increasingly being targeted in cancer therapeutics. Thus, understanding epigenetic regulatory mechanisms lies at the intersection between cancer and cardiovascular disease and is of paramount importance to the burgeoning field of cardio-oncology (Graphic Abstract).