The endoplasmic reticulum (ER) is the primary cell machinery responsible for lipid and protein biosynthesis, protein folding and intracellular calcium storage. Maintaining a homeostatic environment in the ER is vital for normal cellular activities and survival. Undesired changes in cell metabolism disturb the balance between the protein synthesis and folding processes resulting in ER stress. The ability to eliminate ER stress by an intricate set of adaptive signaling pathways, known as unfolded protein response (UPR), is closely correlated with cell function and cell fate. Impaired and/or dysregulated UPR signaling has been implicated in the pathogenesis of various human diseases. The presentation will discuss the impact and mechanisms of ER stress and the UPR signaling in diabetes-related neurovascular injury of the retina and highlight the potential of targeting UPR in the prevention and treatment of diabetic retinopathy.