Cardiovascular disease is the number one cause of death worldwide. A major underlying cause of cardiovascular disease is atherosclerosis – a chronic inflammatory disease of the large arteries. Despite substantial advances over the past few decades, our understanding of the molecular mechanisms that link cardiovascular risk factors to the development and progression of atherosclerosis is incomplete. The endoplasmic reticulum (ER) is a membranous organelle found in all eukaryotic cells that is responsible for protein processing and lipid biosynthesis. In recent years it has become evident that disruptions in ER function are associated with a number of human diseases including atherosclerosis. In this review we examine the potential role of endoplasmic reticulum stress in the initiation and progression of atherosclerosis and discuss possible strategies to target this pathway toward the development of new anti-atherogenic therapies.