The endoplasmic reticulum (ER) contains proteins that carry out the diverse functions of the ER including calcium storage, protein folding, modification, and trafficking, lipid metabolism, and drug detoxification. When soluble ER resident proteins with an ER retention sequence (ERS) depart from the ER they interact with KDEL receptors in the Golgi membrane and are retrogradely transported to the ER lumen via the KDEL receptor retrieval pathway. ER calcium depletion disrupts this process resulting in the mass departure of ERS-containing proteins into the extracellular space. Such a loss of ER resident proteins has two potential consequences to an affected cell. First, there is a loss of proteins involved in the aforementioned critical ER functions. Second, the relocation of such proteins and their associated functions outside of the cell may cause changes in the extracellular environment. This dissertation describes the identification and characterization of a phenomenon whereby ER resident protein secretion is triggered by pathophysiological ER calcium depletion. By exploiting the enzymatic activity of one of the identified ERS-containing proteins we developed an assay to monitor changes in the ER proteome. We also developed a high-throughput screen that identified drugs that could prevent the release of ER resident proteins following ER calcium depletion and showed that several of these compounds have therapeutic potential in models of ER stress and ischemia. Taken together, the work described in my dissertation identifies a novel molecular mechanism of cellular dysfunction for which I have identified both endogenous biomarkers and possible therapeutics.