BACKGROUND: With improved technology, increasing clinical experience, and expanding indications for use, left ventricular assist devices (LVADs) are assuming a greater role in the care of patients with end-stage heart failure. Early in the course of LVAD use as a bridge to transplant, it became evident that some patients exhibit substantial recovery of ventricular function, which led to the concept of reverse remodeling. METHODS AND RESULTS: Herein we summarize and integrate insights derived from a multitude of studies that have investigated how LVAD support influences ventricular structural, cellular, extracellular matrix, molecular, biochemical, and metabolic characteristics of the end-stage failing heart. The focus includes a review of the extent and sustainability of reverse remodeling, the important advances in understanding of the pathophysiology of heart failure derived from these studies and the implications of these findings for development of new therapeutic strategies. CONCLUSION: In brief, studies of LVAD-heart interactions have led to the understanding that although we once considered the end-stage failing heart of patients near death to be irreversibly diseased, when given sufficient mechanical unloading and restoration of more normal neurohormonal milieu, a relatively large degree of myocardial recovery is possible. Comparison of effects on right and left ventricles have provided mechanistic insights by implicating hemodynamic unloading as primarily regulating certain aspects of reverse remodeling, neurohormonal factors as regulating other aspects, and joint regulation of still other aspects. As such these observations have driven a shift of thinking of chronic heart failure as a progressive irreversible disease process to a potentially treatable entity.