Genetic variation and lived experiences shape how our hearts respond to chronic stress. The specific genetic mechanisms which underly cardiac remodeling, however, are still unclear, due in part to the challenge of accounting for environmental effects in human population studies. To overcome this challenge, we used the Collaborative Cross (CC) mouse population to investigate heritable susceptibility to cardiovascular stress by chronic β-adrenergic receptor stimulation. Across 8 founder and 63 CC lines, we measured cardiac structure and function, organ weights, cell and tissue morphology, and left ventricular gene expression. Genome-wide scans detected 49 genome-wide significant loci, collapsing to 20 unique intervals (nine significant for multiple traits and eleven trait-specific), averaging 12.83 Mb in size.