Despite advances in the prevention and management of cardiovascular disease (CVD), this group of multifactorial disorders remains a leading cause of mortality worldwide. CVD is associated with multiple genetic and modifiable risk factors; however, known environmental and genetic influences can only explain a small part of the variability in CVD risk, which is a major obstacle for its prevention and treatment. A more thorough understanding of the factors that contribute to CVD is, therefore, needed to develop more efficacious and cost-effective therapy. Application of the 'omics' technologies will hopefully make these advances a reality. Epigenomics has emerged as one of the most promising areas that will address some of the gaps in our current knowledge of the interaction between nature and nurture in the development of CVD. Epigenetic mechanisms include DNA methylation, histone modification, and microRNA alterations, which collectively enable the cell to respond quickly to environmental changes. A number of CVD risk factors, such as nutrition, smoking, pollution, stress, and the circadian rhythm, have been associated with modification of epigenetic marks. Further examination of these mechanisms may lead to earlier prevention and novel therapy for CVD.