Maintaining homeostasis of Ca2+stores in the endoplasmic reticulum(ER)is crucial for proper Ca2+signaling and key cellular functions.ER,the main intracellular storage medium for Ca2+,is essential for protein folding,secretion,and Ca2+homeostasis.Ca2+depletion induced ER stress has been widely recognized,but the mechanism of ER stress induced by Ca2+depletion has not been well resolved,and little is known whether ER Ca2+overload could induce ER stress.Here,we summarize the latest progress in the ER Ca2+homeostasis and the induction of ER stress.