Clinical heart failure has been defined for a long time as a clinical syndrome with symptoms and signs including shortness of breath, cyanosis, ascites, and edema. However, in recent years, with the thought of promoting early diagnosis and heart-failure prevention, the concept of heart failure has often been defined simply as a subject with severe LV dysfunction and a dilated left ventricle, or by some, defined by evidence of increased circulating levels of molecular markers of cardiac dysfunction, such as ANP and BNP. Heart failure has been considered an irreversible clinical end point. Current medical management for heart failure only relieves symptoms, slows deterioration, and prolongs life modestly. However, in the recent years, rejuvenation of the failing myocardium began to seem possible as the accumulating preclinical studies demonstrated that rejuvenating the myocardium at the molecular and cellular level can be achieved by gene therapy or stem cell transplantation. Here, we review selected novel modalities that have been shown in preclinical studies to exert beneficial effects in animal models of severe LV dysfunction and seem to have the potential to make an impact in the clinical practice of heart-failure management. Antioxid. Redox Signal. 11, 1989-2010.