End-stage heart failure is characterized by a number of abnormalities at the cellular level, which include changes in excitation-contraction coupling, alterations in contractile proteins and activation/deactivation of signaling pathways. Even though many of these changes are adaptive to the high workload and stress in heart failure, a significant number of these alterations are deeply deleterious to the cardiac cell. In this article, we will review the changes in calcium cycling that occur in myopathic hearts and how they can be effectively targeted. We will also focus on protein misfolding in the setting of cardiac dysfunction.