Ferroptosis is a recently described form of regulated necrosis entirely distinct from other forms of cell death. Cysteine availability either through uptake via system xc- or the transsulfuration pathway, glutathione biosynthesis, and proper functioning of GPX4 are the core to prevent iron-dependent lipid peroxidation and ferroptosis. While the role of ferroptosis in physiological contexts remains to be clarified, its contribution to pathophysiological processes including neurodegeneration and ischemia/reperfusion injuries has been demonstrated in animal models of the disease. On the other hand, emerging evidence shows that system xc- is under the direct control of the tumor suppressors p53 and BAP1 as well as IFN-gamma derived from CD8-positive T cells. Additionally, standard therapy-resistant persister tumor cells present a high vulnerability toward ferroptosis, thus providing an Achilles’ heel for therapeutic intervention. Hence, it emerges that sensitizing tumor cells to ferroptosis via cell autonomous and nonautonomous mechanisms may present a “physiological response” to counteract (pre)malignant cells.