Epigenomic mechanisms, such as DNA methylation and histone modifications, represent a critical link between genomic coding and phenotype expression that is influenced by both underlying genetic and environmental factors. Animal models indicate that epigenomic mechanisms have fundamental roles in the development of inflammation, obesity, diabetes, atherosclerotic lesions, and cardiovascular disease. Aberrant DNA methylation and histone modifications have been found in pathology investigations of atherosclerotic lesions. In the present article, we propose an overview of the major milestones in epigenetics, as well as of recent development and technologies for epigenomic research. We review recent findings demonstrating the links of individual characteristics, risk factors, and biomarkers with epigenetic signatures. We present available evidence from human studies that have investigated the relation of epigenetic mechanisms with subclinical and clinical cardiovascular disease. Also, we provide a list of online resources that can help retrieve additional information and facilitate further work in epigenomics. Finally, we discuss open questions for future research in cardiovascular epigenomics, including issues related to the analysis of surrogate and cardiovascular tissues, conduction and analysis of genome-wide epigenetic studies, integration of genomic and transcriptomic data in epigenomic investigations, and perspectives for epigenomics in preventive cardiovascular medicine and pharmacology.