Adult myocardium is a complex tissue in which synchronous beating is ensured by the hierarchical organization and alignment of the functional cardiomyocytes, as guided by the tissue-specific distribution of extracellular matrix (ECM) components. Heart failure (HF) - the end stage of cardiac pathologies in which cardiac muscle is not able to pump adequate blood to the organism – can be described as the mechanical failure of the muscle. HF is driven by a dramatic derangement of the composition, mechanics and nanotopography of cardiac ECM that hinders tissue-specific cell and organ function. In the present study we demonstrate that while cardiomyocyte activity is strictly connected to the ability of the cell to perceive ECM-derived mechanical cues, perturbations in cardiac cell mechanosensing apparatus result in defects in cell maturation and function.The expression of YAP/TAZ, the transcriptional co-activators of Hippo signaling pathway, has been shown to regulate cardiomyocyte proliferation and cardiac morphogenesis during fetal life. Moreover, they also play a role as mechanosensors able to perceive changes in matrix mechanical properties and thus affectstem cell shape, homeostasis and differentiation.By exploiting thermo-responsive polymers in which substrate mechanics and nanotopography can be controlled by tuning temperature within the physiological range, we show that YAP/TAZ intracellular localization in cardiac adult progenitor cells is strongly sensitive to substrate elasticity and depends on cell spreading as a result of cytoskeleton organization. Also, by mimicking the modifications occurring after myocardial infarction in cardiac ECM, we highlight the dynamic response of YAP/TAZ proteins to changes in substrate nanostructure and elasticity. Strikingly, our experiments point at YAP/TAZ as a key axis in the differentiation of adult cardiac progenitor cells. To strengthen this result and further address the role of YAP/TAZ in regulating adult cardiomyocyte function, we generated human cardiomyocytes from induced pluripotent stem cells (iPSC-CMs) and perturbed their ability to perceive the tension arising from the ECM. Indeed, inotropic compounds and pharmacological regulators of cell tension affected YAP/TAZ localization and transcriptional activity in iPSC-CMs. The perturbation of YAP/TAZ activity in iPSC-CMs influenced cardiac contractility and beating rate, while affecting calcium wave propagation.The elucidation of the role of cardiac cell mechanosensors in cell maturation and function could possibly result in the design of novel therapeutic strategies for cardiac pathologies.