Although heart failure is a final common consequence of various heart diseases and is a leading cause of mortality worldwide, the precise molecules and signaling pathways that mediate heart failure progression are largely undefined. In this review, we discuss about the potential mechanisms of heart failure focusing on three subjects, (i) myocardial ischemia, (ii) cardiac muscle cell death, and (iii) abnormalities in calcium handling. These factors are not mutually independent but considered to contribute to the pathogenesis of contractile dysfunction and heart failure in a cooperative manner. Elucidation of molecular mechanisms of heart failure will lead to the development of novel therapeutic strategies for heart diseases.