Resident proteins of the endoplasmic reticulum (ER) lumen carry out many essential cellular functions including lipid metabolism, calcium storage, and protein synthesis and folding. Retention of ER-luminal proteins that are critical to these processes is regulated through their carboxy-terminal ER retention sequence (ERS), such as the canonical KDEL sequence in mammals. KDEL receptors reside in the cis-Golgi and retrogradely transport ERS-containing proteins that escape the ER lumen. The KDEL retrieval pathway has three known KDEL receptors which aid in the retrograde transport of ERS proteins from Golgi to the ER.  We found that under conditions of ER calcium deficiency, the KDEL receptors act as unfolded protein response (UPR) genes that are differentially upregulated by XBP-1 as an adaptive mechanism to counteract the efflux of ERS-containing proteins. Our observations that KDEL receptor expression is transcriptionally regulated by ER stress identifies the retrieval pathway as an adaptive response to minimize the loss of ER luminal proteins, particularly following the disruption of ER calcium homeostasis.  Lastly, we describe how augmentation of KDEL receptor expression may have therapeutic value in diseases associated with ER calcium deficiency.  Overall, we provide new insights into the KDEL retrieval pathway and its role in regulating ER proteostasis.