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Significance: Oxidative folding within the endoplasmic reticulum (ER) introduces disulfide bonds into nascent polypeptides, ensuring proteins' stability and proper functioning. Consequently, this process is critical for maintaining proteome integrity and overall health. The productive folding of thousands of secretory proteins requires stringent quality control measures, such as the unfolded protein response (UPR) and ER-Associated Degradation (ERAD), which contribute significantly to maintaining ER homeostasis. ER-localized protein disulfide isomerases (PDIs) play an essential role in each of these processes, thereby contributing to various aspects of ER homeostasis, including maintaining redox balance, proper protein folding, and signaling from the ER to the nucleus. Recent Advances: Over the years, there have been increasing reports of the (re)localization of PDI family members and other ER-localized proteins to various compartments. A prime example is the anterior gradient (AGR) family of PDI proteins, which have been reported to relocate to the cytosol or the extracellular environment, acquiring gain of functions that intersect with various cellular signaling pathways. Critical Issues: Here, we summarize the functions of PDIs and their gain or loss of functions in non-ER locations. We will focus on the activity, localization, and function of the AGR proteins: AGR1, AGR2, and AGR3. Future Directions: Targeting PDIs in general and AGRs in particular is a promising strategy in different human diseases. Thus, there is a need for innovative strategies and tools aimed at targeting PDIs; those strategies should integrate the specific localization and newly acquired functions of these PDIs rather than solely focusing on their canonical roles. [ABSTRACT FROM AUTHOR]