The study investigates the vulnerability of drug-tolerant persister cancer cells to GPX4 inhibition. Persister cells, which survive cytotoxic treatments through nonmutational mechanisms, are a reservoir for drug-resistant tumors. The authors found that persister cells from various cancers and treatments are dependent on GPX4 for survival. Loss of GPX4 function leads to selective ferroptotic death of persister cells in vitro and prevents tumor relapse in vivo. This suggests that targeting GPX4 could be a therapeutic strategy to prevent acquired drug resistance. The study also highlights the potential of pre- or post-treatment with GPX4 inhibitors to deplete persister cells, potentially improving treatment efficacy while minimizing toxicity.The study investigates the vulnerability of drug-tolerant persister cancer cells to GPX4 inhibition. Persister cells, which survive cytotoxic treatments through nonmutational mechanisms, are a reservoir for drug-resistant tumors. The authors found that persister cells from various cancers and treatments are dependent on GPX4 for survival. Loss of GPX4 function leads to selective ferroptotic death of persister cells in vitro and prevents tumor relapse in vivo. This suggests that targeting GPX4 could be a therapeutic strategy to prevent acquired drug resistance. The study also highlights the potential of pre- or post-treatment with GPX4 inhibitors to deplete persister cells, potentially improving treatment efficacy while minimizing toxicity.