Cells use an exquisite network of mechanisms to maintain the integrity and functionality of their protein components. In the endoplasmic reticulum (ER), these networks of protein homeostasis—referred to as proteostasis—regulate protein synthesis, folding and degradation via the unfolded protein response (UPR) pathway. The UPR pathway has two components: the adaptive UPR pathway, which predominantly maintains the ER function or ER proteostasis, and the apoptotic UPR pathway, which eliminates dysfunctional cells that have been subject to long-term or severe ER stress. Dysregulation of the UPR pathway often occurs in glomerular or tubulointerstitial cells under a pathogenic microenvironment, such as oxidative stress, glycative stress or hypoxia. A defective UPR is highly deleterious to renal cell function and viability and is thereby implicated in the pathophysiology of various kidney diseases. Accumulating evidence provides a link between the UPR pathway and mitochondrial structure and function, indicating the important role of ER proteostasis in the maintenance of mitochondrial homeostasis. Restoration of normal proteostasis, therefore, holds promise in protecting the kidney from pathogenic stresses as well as ageing. This Review is focused on the role of the ER stress and UPR pathway in the maintenance of ER proteostasis, and highlights the involvement of the derangement of ER proteostasis and ER stress in various pathogenic stress signals in the kidney.