The genetics of heart failure is complex. In familial cases of cardiomyopathy, where mutations of large effects predominate in theory, genetic testing using a gene panel of up to 76 genes returned negative results in about half of the cases. In common forms of heart failure (HF), where a large number of genes with small to modest effects are expected to modify disease, only a few candidate genomic loci have been identified through genome-wide association (GWA) analyses in humans. We aimed to use exome sequencing to rapidly identify rare causal mutations in familial cardiomyopathy cases and effectively filter and classify the variants based on family pedigree and family member samples. We identified a number of existing variants and novel genes with great potential to be disease causing. On the other hand, we also set out to understand genetic factors that predispose to common late-onset forms of heart failure by performing GWA in the isoproterenol-induced HF model across the Hybrid Mouse Diversity Panel (HMDP) of 105 strains of mice. We performed fine phenotyping using serial echocardiograms and controlled for environmental heterogeneity in the experimental setting. As a result, we achieved high heritability estimates of 64% to 84% for all cardiac traits and had superior power for mapping HF-related trait, compared to human studies. Association analyses of cardiac traits, corrected for population structure and multiple comparisons, revealed genome-wide significant loci across the spectrum of cardiac traits. Cardiac tissue gene expression profiling, expression quantitative trait loci, expression-phenotype correlation, and coding sequence variation analyses were performed to prioritize candidate genes and to generate hypotheses for downstream mechanistic studies. Future directions will be to further bridge the gap of understanding between rare Mendelian and common cardiovascular diseases, which together will have wide spread therapeutic implications in delaying or reversing HF progression in human populations.