The cardiovascular system is critically important in the transport of oxygen and nutrients in higher organisms. Much is known about the genetic basis for cardiovascular disease and yet it is becoming increasingly clear that we do not fully understand how changes in a patient's genetic makeup affects their cardiovascular function. This dissertation is comprised of several projects related by their investigation of, and applications towards, the multigenic basis for cardiovascular disease. The goal of the first study was to determine the contribution of common genetic variation to establishing human heart rate variability (Chapter 2). We determined that a variant in the 3'-UTR of CYB561 was associated with heart rate variability and elucidated the molecular and functional consequences of microRNA regulation of CYB561 in establishing heart rate. The second study (Chapter 3) describes a novel technique for generating patient- specific induced pluripotent stem cells (iPSCs) with several advantages over exiting methods. We determined iPSCs derived via this method were capable of differentiating into cells of all three germ layers including contractile cardiomyocytes. The third study (Chapter 4) describes the use of iPSC to study the genetic, molecular, and cellular basis for Danon disease in human cardiomyocytes. Cardiomyocytes harboring mutations in the LAMP2 gene exhibited increased mitochondrial oxidative stress, apoptosis, and calcium handling dysregulation. The fourth and final study of this dissertation (Chapter 5) examines the digenic basis for cardiomyopathy within a large family presenting with high rates of dilated cardiomyopathy. We identified novel variants in the genes VINCULIN and TROPOMYOSION1 and determined that these variants cosegregated among all affected family members and combinatorially predispose to dilated cardiomyopathy. We introduced these variants into mice and observed that the combination of these variants results in diminished contractile function of the mouse heart consistent with patient phenotypes. These studies describe new findings concerning the genetic basis for cardiovascular disease and advancing techniques that will enable the further study of genetic interaction of novel variants. A better understanding of the multigenic genetic basis for disease may promote novel therapeutic strategies to help address the worldwide leading cause of morbidity and mortality