The endoplasmic reticulum (ER) plays a crucial role in various cellular activities and cell survival. Almost all of the resident proteins usually enter the ER, and are modified with N-linked glycans and folded into the appropriate secondary and tertiary structures. When cells are faced with stressful conditions, unfolded proteins are accumulated in the ER. The discrepancies between the protein folding capacities and client protein load lead to ER stress. If the stress is prolonged, ER stress responses can activate apoptosis. ER stress-mediated apoptosis is implicated in the pathophysiology of human diseases, including several neurodegenerative diseases, diabetes mellitus, and various infectious diseases. Thus, the ER is now considered as an important organelle that can decide cell survival or death. In this review, the recent progress on ER stress and apoptosis is summarized.