What begins with a failing heart, unable to sustain adequate renal perfusion and metabolic needs of the tissues it serves becomes a systemic illness whose origins are rooted in neurohormonal activation. This unwanted homeostatic stressor response, an adaptation gone awry, has pathologic consequences. It involves endocrine properties of effector hormones arising from the adrenergic and renin-angiotensin-aldosterone systems. The clinical syndrome congestive heart failure (CHF) has its symptoms and signs rooted in a hormonally mediated salt-avid state. The ensuing salt and water retention includes the expansion of the intravascular space with consequent central and systemic venous congestion that, respectively, involves the heart and lungs, the liver, gut and kidneys and ultimately the extravascular space. Other pathophysiologic outcomes contribute to a proinflammatory CHF phenotype. These include an ongoing adverse remodeling of the failing heart with lost necrotic cardiomyocytes and a consequent replacement fibrosis; wasting of soft tissues and resorption of bone; dyshomeostasis of extra- and intracellular mono- and divalent cations that contributes to the appearance of oxidative stress coupled with compromised antioxidant defenses and an immunostimulatory state with activated lymphocytes and monocytes elaborating proinflammatory cytokines. In this 2-part review, the pathophysiologic consequences associated with neurohormonal activation in CHF will first be reviewed. Next, several lines of evidence are considered that raise the hitherto unfathomable prospect for recovery from CHF, including reverse remodeling of the heart and systemic tissues.