The endoplasmic reticulum stress(ERS) has emerged as a factor that is relevant to a number of systemic and arterial-wall factors that promote atherosclerosis(As). Prolonged activation of ERS pathway known as the unfolded protein response (UPR) can lead to cell pathology and subsequent tissue dysfunction. There is now ample evidence that the UPR is chronically activated in atherosclerotic lesional cells, particularly advanced lesional macrophages and endothelial cells. The stressors in advanced lesions that can lead to prolonged activation of the UPR include oxidative stress, oxysterols, and high levels of intracellular cholesterol and saturated fatty acids. These arterial-wall stressors may be especially prominent in the settings of obesity, insulin resistance, and diabetes, all of which promote the clinical progression of As. While exciting work over the last decade has begun to shed light on the mechanisms and in vivo relevance of ERS-driven As, much more work is needed to fully understand this area and to enable an informed approach to therapeutic translation.