<p>Secretory and membrane proteins undergo oxidative folding, the process of forming disulfide bonds between cysteine side chains to construct a stable higher-order structure, primarily in the endoplasmic reticulum (ER) followed by further post-translational modification in the Golgi apparatus, after which proteins proceed to pathways for secretion and membrane localization. Proteins involved in transferring oxidizing power to target proteins possess a pair of highly reactive forms of cysteine residue that mediate reduction-oxidation (redox) reactions. Oxidizing power, which is generally provided in the form of reactive oxygen/reactive nitrogen oxide species. Endoplasmic reticulum oxidoreductin 1 (ERO1) is the ancient ER oxidase that utilizes molecular oxygen to produce hydrogen peroxide, which is then utilized for thiol oxidation to form a disulfide bridge in target proteins. Excessive elevation of these species could promote aberrant oxidation of susceptible molecules, which could lead to an accumulation of misfolded proteins and consequent ER stress. The ER is also involved in cellular Ca²⁺ signaling in which Ca²⁺-pump ATPase and Ca²⁺ release channels coordinate to play essential roles. Ca²⁺ regulates the activity of some redox-reactive proteins, which are largely in the family of protein disulfide isomerase. Thus, the Ca²⁺ status indirectly associates with the oxidative folding of nascent proteins. Upon extensive oxidation, inactivation of the Ca²⁺-pump ATPase and inappropriate Ca²⁺ leak via the Ca²⁺ channels causes a depletion of Ca²⁺ in the ER lumen. When intracellular calcium is depleted, stromal interaction molecules (STIM) in the ER membrane sense the Ca²⁺ status within the ER lumen. STIM differentially regulates two types of Ca²⁺ channels in the plasma membrane: Ca²⁺-release-activated Ca²⁺ channel (ORAI), and voltage-operated Ca²⁺ channel (CaV1.2). This regulation coordinately maintains Ca²⁺ homeostasis within cells. Moreover, Zn²⁺ and H⁺ indirectly affect the potential of redox responses through controlling ER chaperone molecules. The redox capacity of the ER is maintained by resident proteins and small compounds, which include cations Ca²⁺, Zn²⁺ and H⁺, and hence the comprehensive care of them is necessary in order to maintain normal ER function.</p>