Heart failure is one of the most elusive diseases to treat let alone cure. While deaths due to heart failure have significantly declined, for the first time in decades they’re back on the rise. Contributing to this increase is our poor understanding of how extracellular matrix (ECM) remodeling or fibrosis impacts cardiac cell behavior and phenotypic outcome. This remodeled ECM environment not only impacts the disease process but also stem cell based interventions, which to date hold the most promise for reversing heart disease. Stem cell-derived cardiac muscle cells cultured on engineered ECM scaffolds have demonstrated that matrix substrate, alignment, and elasticity influence their fate, structure and function, yet these relationships have not been directly examined using diseased scaffolds or in the native cardiac environment replete with physiologic scaling and cell-matrix/cell-cell interactions. If regenerative interventions are to become a bona fide solution for treating heart disease, understanding how stem-cell derived muscle cell grafts behave in the diseased matrix environment is critical for improving the efficacy of these therapeutic strategies. Using a mouse genetics approach for rationally and precisely tuning the ECMs properties we will examine the understudied symbiotic relationship between cardiac muscle cells and the ECM in the context of cardiac repair and regeneration by addressing two vital unknowns: (1) how the properties of cardiac matrix scaffolds obtained from heart failure patients influences induced pluripotent stem cell (IPSC) and human embryonic stem cell (hESC) derived cardiac muscle cell behavior, and (2) how ECM composition impacts native cardiac repair and regeneration. Addressing these goals could yield paradigm shifts in both the basic science and translational medicine as they will reveal whether the heart’s ECM is more than a passive structural element but rather functions as a hub of information that directs cardiac muscle cell fate, structure and function. We anticipate these results will initiate a rich new research direction into developing in vivo “Precision Matrices” for beneficially treating disease and/or improving current cardiac regenerative therapies.