The endoplasmic reticulum (ER) is a multifunctional organelle that accommodates a large array of functions. Recent publications have shown that many of these functions are influenced by the ongoing oxidative folding of secretory and membrane proteins. Conversely, successful ER protein folding critically depends on the cellular redox state, but also the availability of Ca²⁺. These findings suggest the existence of regulatory mechanisms that steer ER Ca²⁺ homeostasis according to the cellular redox state. Indeed, accumulating evidence demonstrates that ER Ca²⁺ uptake and release by sarco-endoplasmic reticulum Ca²⁺ transport ATPases (SERCAs), stromal interaction molecule 1 (STIM1), Orai1, inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) and ryanodine receptors (RyR) depends on redox modifications of these channels and pumps. In addition, ER chaperones and oxidoreductases moonlight as regulators of ER Ca²⁺ channels and pumps. Discrete redox conditions of channels, pumps and oxidoreductases exist that allow for opening and closing. Through these functions, redox regulation of ER Ca²⁺ influences signaling mechanisms governing cell growth and migration, apoptosis and mitochondrial energy production. Therefore, pharmacological intervention based on ER redox or on ER redox-sensitive chaperones and oxidoreductases is a promising strategy to influence all metabolic syndromes including cancer and neurodegeneration.