Ferroptosis is a form of regulated cell death caused by iron-dependent lipid peroxidation. Glutathione-dependent lipid hydroperoxidase, glutathione peroxidase 4 (GPX4), prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols. However, the sensitivity to GPX4 inhibitors varies among cancer cell lines, suggesting additional factors govern resistance to ferroptosis. Using a synthetic lethal CRISPR/Cas9 screen, the authors identify ferroptosis suppressor protein 1 (FSP1) as a potent ferroptosis resistance factor. FSP1, previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2), is recruited to the plasma membrane by myristoylation and functions as an oxidoreductase that reduces coenzyme Q10 (CoQ) to generate lipophilic radical-trapping antioxidants (RTAs) that halt lipid peroxide propagation. FSP1 expression correlates positively with ferroptosis resistance across hundreds of cancer cell lines and mediates resistance in lung cancer cells in culture and mouse tumor xenografts. These findings identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway, providing a new therapeutic strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutics.Ferroptosis is a form of regulated cell death caused by iron-dependent lipid peroxidation. Glutathione-dependent lipid hydroperoxidase, glutathione peroxidase 4 (GPX4), prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols. However, the sensitivity to GPX4 inhibitors varies among cancer cell lines, suggesting additional factors govern resistance to ferroptosis. Using a synthetic lethal CRISPR/Cas9 screen, the authors identify ferroptosis suppressor protein 1 (FSP1) as a potent ferroptosis resistance factor. FSP1, previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2), is recruited to the plasma membrane by myristoylation and functions as an oxidoreductase that reduces coenzyme Q10 (CoQ) to generate lipophilic radical-trapping antioxidants (RTAs) that halt lipid peroxide propagation. FSP1 expression correlates positively with ferroptosis resistance across hundreds of cancer cell lines and mediates resistance in lung cancer cells in culture and mouse tumor xenografts. These findings identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway, providing a new therapeutic strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutics.