The endoplasmic reticulum (ER) is an organelle present in most eukaryotic cells and plays a pivotal role in lipid metabolism. ER dysfunction, specifically ER stress (ERS), is a pathophysiological response involved in lipid metabolism and cardiovascular lesions. Therefore, suppression of ERS may improve lipid metabolic disorders and reduce cardiovascular risk. Herein, we focus on novel breakthroughs regarding the roles of ERS in lipid metabolism and cardiovascular disease (CVD), as well as the internal mechanisms of ERS and its status as a potential therapeutic target. This review highlights recent advances in ERS, the regulation of which might be helpful for both basic research and clinical drug design for lipid metabolic disorders and CVD.