Chronic heart failure is a debilitating condition with significant morbidity, mortality and an increasing economic burden. The past 20 years have witnessed great strides in both medical and device-based therapies for heart failure. Central to these developments has been the ability to favorably reverse the chronic processes by which the failing heart remodels. In addition to pharmacotherapies, such as beta-blockade, and inhibition of the renin-angiotensin-aldosterone system, surgical remodeling, containment devices and new methods to restore synchronous contraction have been added to the armamentarium, in some instances, providing clear improvement to both symptoms and mortality. In more advanced stages of heart failure, left ventricular-assist devices provide marked unloading of the failing ventricle and such therapy has provided unique insights into the molecular and cellular mechanisms underlying reverse remodeling, given the immediate access to cardiac tissue. Genetic and cellular approaches, as well as new small molecule targets, may provide future avenues for reverse remodeling of the failing heart, improving symptoms and disease outcome.