Significance: Diabetes and other diseases that comprise the metabolic syndrome have reached epidemic proportions. Diabetic peripheral neuropathy (DPN) is the most prevalent complication of diabetes, affecting ∼50% of diabetic patients. Characterized by chronic pain or loss of sensation, recurrent foot ulcerations, and risk for amputation, DPN is associated with significant morbidity and mortality. Mechanisms underlying DPN pathogenesis are complex and not well understood, and no effective treatments are available. Thus, an improved understanding of DPN pathogenesis is critical for the development of successful therapeutic options. Recent Advances: Recent research implicates endoplasmic reticulum (ER) stress as a novel mechanism in the onset and progression of DPN. ER stress activates the unfolded protein response (UPR), a well-orchestrated signaling cascade responsible for relieving stress and restoring normal ER function. Critical Issues: During times of extreme or chronic stress, such as that associated with diabetes, the UPR may be insufficient to alleviate ER stress, resulting in apoptosis. Here, we discuss the potential role of ER stress in DPN, as well as evidence demonstrating how ER stress intersects with pathways involved in DPN development and progression. An improved understanding of how ER stress contributes to peripheral nerve dysfunction in diabetes will provide important insight into DPN pathogenesis. Future Directions: Future studies aimed at gaining the necessary insight into ER stress in DPN pathogenesis will ultimately facilitate the development of novel therapies. Antioxid. Redox Signal. 21, 621-633. [ABSTRACT FROM AUTHOR]