The interaction of the endoplasmic reticulum (ER) with mitochondria, which occurs on the mitochondria-associated membrane (MAM), is necessary for the ER to carry out its main functions of protein and lipid production and Ca2+ storage. The MAM itself is the central intracellular Ca2+ signalling structure, and although it is known that various ER chaperones and oxidoreductases regulate ER–mitochondria Ca2+ exchange, the molecular machinery involved in ER–mitochondria Ca2+ signalling is poorly understood. Calnexin is a key ER chaperone that is found on the rough ER where it exerts a quality control function; it is also often found, however, on the MAM, suggesting a central role in regulating ER Ca2+ signalling. Thomas Simmen and colleagues have previously shown that palmitoylation of calnexin enriches calnexin on the MAM, and now (p. 3893), they investigate the functional significance of this palmitoylation-dependent targeting. The authors show that palmitoylated calnexin interacts with the sarcoendoplasmic reticulum Ca2+ transport ATPase (SERCA) 2b Ca2+ pump, and that this interaction determines the Ca2+ content of the ER and regulates ER–mitochondria Ca2+ crosstalk. Non-palmitoylated calnexin, however, preferentially interacted with the oxidoreductase ERp57 (also known as PDIA3) to perform its quality control function. Moreover, the authors show that palmitoylation of calnexin is also an ER-stress-dependent mechanism: short-term ER stress results in the depalmitoylation of calnexin, which shifts its function from Ca2+ signalling regulation to substrate chaperoning and quality control. These results, therefore, identify palmitoylation as the switch that assigns calnexin to either Ca2+ signalling or to protein quality control.