Despite remarkable advances in medical therapeutics and technology over the last 40 yr, cardiovascular disease remains the leading cause of mortality in the United States. Elucidation of the human genome and the application of gene mapping techniques to kindreds harboring rare monogenic cardiovascular syndromes have provided fundamental insights into the pathogenesis of common cardiovascular diseases including hypertension, hypercholesterolemia, cardiomyopathy with and without conduction system disease, cardiac arrhythmias, and most recently congenital heart disease. These findings led to the unanticipated conclusion that common cardiovascular pathologies (e.g. cardiomyopathy, congenital heart disease, hypertension, cardiac arrhythmias) are united by association with distinct subsets of genes. In this review, the impact of these data on the molecular pathogenesis and development of future therapies for cardiomyopathy, congenital heart disease, and atherosclerosis are highlighted. In addition, the application and limitations of evolving genetic and genomic technologies to acquired and/or multigenic cardiovascular states including atherosclerosis and high density lipoprotein (HDL) metabolism is discussed.