Cardiovascular disease (CVD) affects many people in the United States. Compared with other population groups in the United States, epidemiologic data suggest that Hispanic Americans are at a disproportionate risk for CVD. The etiology of this disparity is complex, with genetic, behavioral, cultural, and other environmental factors acting in an independent, interactive, and/or synergistic fashion. Because many complex conditions mediate risk of CVD, including diabetes, obesity, and hyperlipidemia, genes associated with these conditions have been considered as possible contributors to CVD in Hispanics. In addition, the diversity of background and heritage within this population creates a plethora of environmental determinants that interact with behaviors, cultural practices, and genetic makeup to influence disease risk. In this review, we explore the recent literature on genetic determinants of CVD and explain that effective efforts to reduce CVD disparities in Hispanics in the United States will require an understanding of the interactions of genes, the environment, and health-related practices.