The endoplasmic reticulum(ER) is crucial for protein and lipid synthesis, folding and cellular homeostasis. Function impairment of ER would induce ER stress, which might play an important role in many different pathological states. Small heat shock proteins (sHsps) are known to be widely expressed throughout many tissues. SHsps are found to regulate many different pathological and pathophysiological processes and they are supposed to be potential therapeutic targets. Recent studies indicate that multiple sHsps localize to the mammalian and plant ER and sHsps confer protection against ER stress in multiple cellular processes. The mechanisms responsible for the cytoprotective effects of sHsps are related to maintaining ER homeostasis. Improved understanding of sHsps-related cytoprotective action on ER and successful strategies which could specifically target components of ER stress signalling responses amelioration of their toxic effects by sHsps is of great importance in the development of therapeutic approach for the disorders induced by dysfunction of ER.