Three decades ago, investigators studying the function of the endoplasmic reticulum (ER) focused on its role in transiently regulating Ca2+ concentrations in cardiovascular cells. Muscle cells, including cardiomyocytes, contain a specialized smooth ER, the sarcoplasmic reticulum, and Ca2+ release and reuptake by the sarcoplasmic reticulum trigger the contraction and relaxation of the myofibrils, respectively. Cardiovascular research has been focused on many aspects of muscle physiology, including myocardial contractility and relaxation, to better understand the regulation of systemic and cardiac hemodynamics. Furthermore, accumulating evidence indicates that perturbation in Ca2+ homeostasis contributes to cardiovascular disease and is an effective therapeutic target for the treatment of heart disease. While intracellular Ca2+ homeostasis was being investigated in great detail, a major discovery in ER biology was made in 1988, with the first description of the ER-stress response. 1 Although cardiovascular researchers did not initially enter this field, there has been a large shift in cardiovascular research toward this topic over the past several years. To assess the significance of these findings, we must consider the functions of the ER. Cellular homeostasis and function require properly folded proteins. Protein folding is the process by which a linear polymer of amino acids acquires a unique 3D structure (the native conformation) capable of performing its cellular function (s). During the folding process, proteins often interact with molecular chaperones that bind to the hydrophobic regions of unfolded or incompletely folded proteins to facilitate proper folding but, perhaps more importantly, prevent the accumulation of misfolded proteins in toxic aggregates. Throughout their lifetime, cells are exposed to a range of environmental stressors, such as radiation, hypoxia, heat, osmotic shifts, and oxidation, and all of these can lead to the adoption of aberrant 3D structures in damaged proteins. 2 Cells carefully monitor for the presence of misfolded proteins in different compartments. The accumulation of misfolded proteins in the cytosol triggers a heat-shock response, which stimulates the transcription of genes encoding cytosolic chaperones to refold destabilized proteins. Similarly, the accumulation of misfolded proteins in the ER initiates a signaling cascade from the ER to the nucleus that induces a comprehensive gene expression program to increase the protein folding capacity of the cell according to need. 3 However, the mechanism and pathways that are essential for the ER to nucleus signaling were entirely unknown for quite some time.