SAL1, as a negative regulator of stress response signaling, has been studied extensively for its role in plant response to environmental stresses. However, the role of SAL1 in cadmium (Cd) stress response and the underlying mechanism is still unclear. Using an Arabidopsis thalianaloss-of-function mutant of SAL1, we assessed Cd resistance and further explored the Cd toxicity mechanism through analysis of the endoplasmic reticulum (ER) stress response. The loss of SAL1 function greatly improved Cd tolerance and significantly attenuated ER stress in Arabidopsis. Exposure to Cd induced an ER stress response in Arabidopsis as evidenced by unconventional splicing of AtbZIP60 and up-regulation of ER stress-responsive genes. Damage caused by Cd was markedly reduced in the ER stress response double mutant bzip28 bzip60 or by application of the ER stress-alleviating chemical agents, tauroursodeoxycholic acid (TUDCA) and 4-phenyl butyric acid (4-PBA), in wild-type plants. The Cd-induced ER stress in Arabidopsis was also alleviated by loss of function of SAL1. These results identified SAL1 as a new component mediating Cd toxicity and established the role of the ER stress response in Cd toxicity. Additionally, the attenuated ER stress in the sal1 mutant might also shed new light on the mechanism of diverse abiotic stress resistance in the SAL1 loss-of-function mutants.