Since the discovery of the cardiac hormone atrial natriuretic peptide by de Bold and colleagues in 1981, the field of natriuretic peptides has significantly advanced with translation of new knowledge to the clinical practice of heart failure. This new knowledge builds on the importance of cardiorenal mechanisms that contribute to optimal cardiovascular regulation. Recent investigations by our group and others have also established the direct myocardial actions of the natriuretic peptides, broadening their therapeutic potential beyond renal mechanisms. Indeed, a potential therapeutic target is cardiac remodeling and fibrosis based on the unique cardiorenal and humoral protective properties that natriuretic peptides possess. We review new insights into the natriuretic peptide system and specifically focus on the possible role of natriuretic peptides as a new therapeutic strategy to limit cardiac remodeling and fibrosis to delay worsening of cardiac function and the progression of heart failure.