The endoplasmic reticulum stress (ERS) is a kind of adaptive response of cells to the alteration of internal and external environments, which contributes to the cells survival. However, it can eventually trigger cell apoptosis once ER dysfunction is severe or prolonged. ERS is intensively induced during ischemia/reperfusion by Ca2+ disturbance, oxidative stress, and so on. Ischemic preconditioning and Ca2+ homeostasis steadying can induce proper ERS, which enhances cell tolerance to prolonged ischemia stimulation, and leads to mitigation of I/R injury. This article reviewed the roles of the ERS in IRI, and proposed that ERS has become a possible target for IRI prevention and cure.