ARID1A encodes an SWI/SNF chromatin-remodeling factor and is frequently mutated in various cancers. This study demonstrates that ARID1A-deficient cancer cells are specifically vulnerable to inhibition of the antioxidant glutathione (GSH) and the glutamate-cysteine ligase synthetase catalytic subunit (GCLC), a rate-limiting enzyme for GSH synthesis. Inhibition of GCLC markedly decreased GSH in ARID1A-deficient cancer cells, leading to apoptotic cell death triggered by excessive amounts of reactive oxygen species. The vulnerability of ARID1A-deficient cancer cells results from low basal levels of GSH due to impaired expression of SLC7A11. The SLC7A11-encoded cystine transporter supplies cells with cysteine, a key source of GSH, and its expression is enhanced by ARID1A-mediated chromatin remodeling. Thus, ARID1A-deficient cancers are susceptible to synthetic lethal targeting of GCLC. Display omitted •ARID1A maintains GSH homeostasis by enhancing SLC7A11 transcription•Low SLC7A11 expression causes low basal GSH levels in ARID1A-deficient cancer cells•Inhibiting GSH/GCLC in ARID1A-deficient cancer cells causes apoptosis by ROS•GCLC is a druggable synthetic lethal target for ARID1A-deficient cancer Ogiwara et al. show that ARID1A-deficient cancer cells express low levels of the key cystine transporter SLC7A11 and thus have low basal levels of glutathione (GSH), which make these cancer cells specifically vulnerable to inhibition of the GSH metabolic pathway.