Depression is a devastating mood disorder that causes profound disability worldwide. Despite the increasing number of antidepressant medications available, the treatment options for depression are limited. Therefore, understanding the etiology and pathophysiology of depression, and exploiting potential novel agents to treat and prevent this disorder are imperative. Endoplasmic reticulum (ER) stress activates the unfolded protein response and mediates the pathogenesis of psychiatric diseases, including depression. Emerging evidence in human and animal models suggests an intriguing link between ER stress and depression. The ER serves as an important subcellular organelle for the synthesis, folding, modification, and transport of proteins, a process that is highly developed in neuronal cells. Perturbations of ER homeostasis lead to ER stress, and ER stress helps to restore the normal ER function by restoring the protein‑folding capacity of the ER. This biological defense mechanism is imperative to prevent the disease. However, excessive or persistent ER stress eventually causes cell death. If the damage occurs in the hippocampus, the amygdala and striatum and other areas of the neurons will be involved in the development of depression. In this review article, we explore how ER stress might have an important role in the pathophysiology of depression and how different drugs affect depression through ER stress.