By unloading the failing myocardium and permitting tissue-based investigations before and after unloading, recent clinical use of ventricular assist devices (VADs) has provided a unique window into the pathophysiology of advanced heart failure in humans. Work to date has provided novel insights into the load-dependent modulation of myocardial hypertrophy, contractility, calcium homeostasis, adrenergic responsiveness, bioenergetics, cytokines, and gene expression. In general, the documented effects of VAD support on the failing heart have been diverse and often dramatic. Moreover, the phenotypic shifts observed have typically tended toward a less pathologic state than that associated with the refractory hypertrophy and heart failure that necessitated VAD implantation. The most striking feature of the composite body of work thus far accumulated in this area is the demonstration that even the most diseased human hearts exhibit the capacity for profound phenotypic plasticity when subjected to sufficient reductions in cardiac loading conditions and neurohormonal stimulation.