Cardiovascular disease (CVD) retains a leadership as a major cause of human death worldwide. Although a substantial progress was attained in the development of cardioprotective and vasculoprotective drugs, a search for new efficient therapeutic strategies and promising targets is under way. Modulation of epigenetic CVD mechanisms through administration epigenetically active agents is one of such new approaches. Epigenetic mechanisms involve heritable changes in gene expression that are not linked to the alteration of DNA sequence. Pathogenesis of CVDs is associated with global genome-wide changes in DNA methylation and histone modifications. Epigenetically active compounds that influence activity of epigenetic modulators such as DNA methyltransferases (DNMTs), histone acetyltransferases, histone deacetylases (HDACs), etc. may correct these pathogenic changes in the epigenome and therefore be used for CVD therapy. To date, many epigenetically active natural substances (such as polyphenols and flavonoids) and synthetic compounds such as DNMT inhibitors or HDAC inhibitors are known. Both native and chemical DNMT and HDAC inhibitors possess a wide range of cytoprotective activities such as anti-inflammatory, antioxidant, anti-apoptotic, anti-anfibrotic, and anti-hypertrophic properties, which are beneficial of treatment of a variety of CVDs. However, so far, only synthetic DNMT inhibitors enter clinical trials while synthetic HDAC inhibitors are still under evaluation in preclinical studies. In this review, we consider epigenetic mechanisms such as DNA methylation and histone modifications in cardiovascular pathology and the epigenetics-based therapeutic approaches focused on the implementation of DNMT and HDAC inhibitors.