The endoplasmic reticulum (ER) is the site of lipid and protein synthesis, protein folding and maturation, and storage of free calcium in eukaryotic cells. All proteins destined for the extracellular space, plasma membrane or other intracellular compartments are folded and assembled in the ER. Disruption of the ER homeostatic mechanisms, such as perturbations in intracellular calcium homeostasis, alteration of redox status and protein glycosylation, overloading of free cholesterol, or glucose deprivation, will induce accumulation of unfolded and misfolded proteins in the ER lumen. Mammalian cells respond to these perburbations by activating the ER stress response signaling pathway, called the unfolded protein response (UPR). This cellular stress pathway is designed to cope with various environmental perturbations and ensure that protein-folding capacity is not overwhelmed. The malfolded proteins are eliminated by ERassociated protein degradation (ERAD). However, prolonged activation of the UPR ultimately triggers cell apoptosis. Recent studies have demonstrated that ER stress-induced apoptosis plays a critical role in the pathogenesis of many diseases such as diabetes, neurodegenerative diseases, inflammation, liver disease, and cardiovascular disease. This review summarizes the recent understanding of ER stress signaling in the pathogenesis of atherosclerosis.