In this review, we discuss (1) the relationship between ER stress and pancreatic β-cell dysfunction in diabetes, (2) UPR-related gene variants as risk factors for the development of T2DM, (3) the role of the WFS1 gene and its contribution to the development of Wolfram syndrome and T2DM, and (4) the opportunities for clinical application of ER stress reducers and induced pluripotent stem cell (iPSC)-based treatment against T2DM and monogenic forms of diabetes. Here, WFS1 is linked to type 2 diabetes mellitus.