Bak and Bax (Bak/Bax) play overlapping and essential roles in mitochondrial apoptosis, and Bak/Bax deficiency can confer tumour cells with resistance to conventional therapies that trigger this cell-death pathway. Ute Fischer and colleagues (p. 4481) now report that Bak/Bax-deficient cells can be killed by specific inhibitors of the sarco-endoplasmic reticulum ATPase (SERCA) pump, which transports Ca2+ into the ER. They show that treatment with the SERCA inhibitor thapsigargin depletes ER Ca2+ stores in Bak/Bax-deficient murine embryonic fibroblasts (MEFs), thereby inducing ER stress and triggering caspase-independent necrotic cell death. Wild-type MEFs are also killed by thapsigargin, but by a caspase-dependent apoptotic pathway. Cell death induced by thapsigargin in Bak/Bax-deficient MEFs does not appear to involve the main regulators of the unfolded protein response that is triggered in response to ER stress (such as PERK, ATF6 or IRE1α); rather, thapsigargin causes excess mitochondrial Ca2+ uptake, loss of membrane potential and irreversible mitochondrial damage. Finally, the authors show that thapsigargin also induces necrosis in Bak/Bax-deficient colon and prostate carcinoma cells. These results indicate that SERCA inhibition is a promising therapeutic strategy to treat multidrug-resistant tumours, and highlight the importance of the ER as a cell-death regulator.