Heart failure is an increasingly prevalent cause of significant worldwide morbidity, mortality, and economic burden. Molecular investigations are unraveling the gene expression changes, protein signaling networks, and intercellular interactions that are causes and consequences of cardiac hypertrophy and failure. In particular, reactivation of the “fetal gene program” that is silenced in the normal adult heart has come to define the pathologic hypertrophic cardiac response that leads to heart failure. Our evolving knowledge of the molecular and cellular changes in the failed myocardium—for example, alterations in calcium signaling—is leading to new therapeutic options. This chapter summarizes some of the current understanding of changes responsible for cardiac hypertrophy, cardiomyocyte death, and altered cardiac metabolism. It also discusses emerging biomarkers for profiling of heart failure severity.