Heart failure (HF) involves changes in cardiac structure, myocardial composition, myocyte deformation, and multiple biochemical and molecular alterations that impact heart function and reserve capacity. Collectively, these changes have been referred to as ‘cardiac remodeling’. Understanding the components of this process with the goal of stopping or reversing its progression has become a major objective. This concept is often termed ‘reverse remodeling’, and is successfully achieved by inhibitors of the renin-angiotensin-aldosterone system, β-blockers, and device therapies such as cardiac resynchronization or ventricular assist devices. Not every method of reverse remodeling has long-lasting clinical efficacy. However, thus far, every successful clinical treatment with long-term benefits on the morbidity and mortality of patients with HF reverses remodeling. Reverse remodeling is defined by lower chamber volumes (particularly end-systolic volume) and is often accompanied by improved β-adrenergic and heart-rate responsiveness. At the cellular level, reverse remodeling impacts on myocyte size, function, excitation-contraction coupling, bioenergetics, and a host of molecular pathways that regulate contraction, cell survival, mitochondrial function, oxidative stress, and other features. Here, we review the current evidence for reverse remodeling by existing therapies, and discuss novel approaches that are rapidly moving from preclinical to clinical trials.