The endoplasmic reticulum (ER) performs multiple functions in the cell: it is the major site of protein and lipid synthesis as well as the most important intracellular Ca²⁺ reservoir. Adverse conditions, including a decrease in the ER Ca²⁺ level or an increase in oxidative stress, impair the formation of new proteins, resulting in ER stress. The subsequent unfolded protein response (UPR) is a cellular attempt to lower the burden on the ER and to restore ER homeostasis by imposing a general arrest in protein synthesis, upregulating chaperone proteins and degrading misfolded proteins. This response can also lead to autophagy and, if the stress can not be alleviated, to apoptosis. The inositol 1,4,5-trisphosphate (IP₃) receptor (IP₃R) and IP₃-induced Ca²⁺ signaling are important players in these processes. Not only is the IP₃R activity modulated in a dual way during ER stress, but also other key proteins involved in Ca²⁺ signaling are modulated. Changes also occur at the structural level with a strengthening of the contacts between the ER and the mitochondria, which are important determinants of mitochondrial Ca²⁺ uptake. The resulting cytoplasmic and mitochondrial Ca²⁺ signals will control cellular decisions that either promote cell survival or cause their elimination via apoptosis. This article is part of a Special Issue entitled: 12th European Symposium on Calcium.