Endoplasmic reticulum (ER) is an organelle intimately involved in control of cell activities through Ca(2+) signaling, as well as in post-translational protein folding and maturation. Ca(2+) storage within the ER is required for both of these functions. Several of the ER-resident proteins essential for the protein folding pathway require Ca(2+) binding for their activity. A number of factors, including Ca(2+) depletion, may interfere with the folding pathway within the ER, with a potential for cell injury through an accumulation of malfolded protein aggregates. The Unfolded Protein Response involves a transcriptional upregulation of a number of the ER-resident folding helper proteins and becomes triggered when the folding pathway is blocked. To be effective, these upregulated proteins require a sufficient supply of Ca(2+) cofactor within the ER lumen. In tissue ischemia, where the availablity of this cofactor may be compromised, the newly described ability of the cell to boost the ER Ca(2+)-loading capacity by upregulating the ER Ca(2+) pump may be of particular importance for limiting cell injury and promoting survival. The novel focus on the pathophysiological significance of ER Ca(2+)depletion extends the scope of disturbed Ca(2+) homeostasis following ischemia beyond the consequences of the cytosolic calcium overload.