Cardiovascular disease (CVD) is the leading cause of death in both men and women and has largely been attributed to genetic makeup and lifestyle factors. However, genetic regulation does not fully explain the pathophysiology. Recently, epigenetic regulation, the regulation of the genetic code by modifications that affect the transcription and translation of target genes, has been shown to be important. Silent information regulator-2 proteins or sirtuins are an epigenetic regulator family of class III histone deacetylases (HDACs), unique in their dependency on coenzyme NAD+, that are postulated to mediate the beneficial effects of calorie restriction, thus promoting longevity by reducing the incidence of chronic diseases such as cancer, diabetes, and CVD. Emerging evidence shows that SIRT1 is ubiquitously expressed throughout the body. Resveratrol, a plant polyphenol, has cardioprotective effects and its mechanism of action is attributed to regulation of SIRT1. Incoproation of resveratrol into the diet may be a powerful therapeutic option for the prevention and treatment of CVD.