This review evaluates the role of mechanotransduction (MT) in heart failure (HF) pathobiology. Cardiac functional and structural modifications are regulated by biomechanical forces. Exposing cardiomyocytes and the myocardial tissue to altered biomechanical stress precipitates changes in the end-diastolic wall stress (EDWS). Thereby various interconnected biomolecular pathways, essentially mediated and orchestrated by MT, are launched and jointly contribute to adapt and remodel the myocardium. This cardiac MT-mediated feedback decisively determines the primary cardiac cellular and tissue response, the sort (concentric or eccentric) of hypertrophy/remodeling, to mechanical and/or hemodynamic alterations. Moreover, the altered EDWS affects the diastolic myocardial properties independent of the systolic function, and elevated EDWS causes diastolic dysfunction. The close interconnection between MT pathways and the cell nucleus, the genetic endowment, principally allows for the wide variety of phenotypic appearances. However, demographic, environmental features, comorbidities, and also the genetic make-up may modulate the phenotypic result. Cardiac MT takes a fundamental and superordinate position in the myocardial adaptation and remodeling processes in all HF categories and phenotypes. Therefore, the effects of MT should be integrated in all our scientific, clinical, and therapeutic considerations.