This review is concerned with cardiac malfunction as a result of an imbalance in protein proteostasis, the homeostatic balance between protein removal and regeneration in a long remodeling process involving the endoplasmic reticulum (ER) and the unfolded protein response (UPR). The importance of this is of special significance with regard to cardiac function as a high energy requiring muscular organ that has a high oxygen requirement and is highly dependent on mitochondria. The importance of mitochondria is not only concerned with high energy dependence on mitochondrial electron transport, but it also has a role in the signaling between the mitochondria and the ER under stress. Proteins made in the ER are folded as a result of sulfhydryl groups (−SH) and attractive and repulsive reactions in the tertiary structure. We discuss how this matters with respect to an imbalance between muscle breakdown and repair in a stressful environment, especially as a result of oxidative and nitrosative byproducts of mitochondrial activity. The normal repair is a remodeling, but under this circumstance, the cell undergoes or even lysosomal “self eating” autophagy, or even necrosis instead of apoptosis. We shall discuss the relationship of the UPR pathway to chronic congestive heart failure (CHF). The left ventricular wall thickening is correlated with phosphorylated eIF2/eIF2 ratio and level of dysregulation of calcium‐handling proteins, including, P‐ryanodine receptor, Ca2+ storing protein calsequestrin, Na‐Ca2+ exchanger, sarcoendoplasmic reticulum Ca2+‐ATPase (SERCA2α), ER chaperone protein calreticulin. The UPR occurs as a protein unfolding with the breaking of sulfhydryl groups in the tertiary structure. If the stress on proteostasis is for an extended period, the ability to repair may be compromised. Consequently, the opened protein skeletons may aggregate and when the stress is sufficient, the transport of protein is disabled and protein occludes the ER canal. GRP78 (also known as BiP) is a heat‐shock protein chaperone resident in the ER that binds and blocks three sensor proteins present in the ER membrane in the basal stress conditions. In unstressed conditions, binds to PERK, ATF6, and inositol‐requiring protein‐1α (IRE1α). GRP78 shifts from blocking the sensor proteins to binding the unfolded proteins, triggering UPR when unfolded protein accumulates in the ER lumen. When there is a mild stress, unfolded protein accumulates, and universal protein synthesis is inhibited and it resumes upon recovery. Activated IRE1α then splices X‐box binding protein‐1 (XBP‐1) mRNA, which leads to synthesis of the active transcription factor XBP‐1 and upregulation of UPR genes. Active ATF6 translocates from the ER to Golgi where it activates genes to increase ER protein folding. Once activated three sensor proteins PERK, IRE1α, and ATF6 lead to inhibition of translation and increased transcription of chaperones, stress response genes, and redox‐related genes. PERK phosphorylates the translation initiation factor eIF2α, thereby inhibiting global translation and reducing the load of newly synthesized. eIF2α phosphorylation allows ATF4 translation, a transcriptional activator that induces a cascade that ultimately produces proapoptotic factors. A more severe or persistent stress would lead to apoptosis.