As part of an international team effort, we reveal that blocking IRE1, a key component of the unfolded protein response (UPR), counterbalances atherosclerosis progression in a mouse model. The UPR is the stress response network of the endoplasmic reticulum. This study is proof-of-concept that the pharmacological targeting of the UPR can bring therapeutic benefit in this disease, and brings us one step closer to understanding the wiring of cellular stress response networks in health and disease.