Ferroptosis has emerged as an attractive strategy in cancer therapy. Understanding the operational networks regulating ferroptosis could unravel vulnerabilities that can be harnessed for therapeutic benefit. Using CRISPR-activation screens in ferroptosis hypersensitive cells, we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis. Genetic deletion of LRP8 leads to ferroptosis due to an insufficient supply of selenocysteine, which is required for the translation of the anti-ferroptotic selenoprotein GPX4. This lineage dependency is caused by low expression of alternative selenium uptake pathways such as system Xc-. The identification of LRP8 as a specific vulnerability of MYCN-amplified neuroblastoma cells was confirmed in constitutive and inducible LRP8 knockout orthotopic xenografts. These findings disclose that cancer cells can rewire selenium uptake pathways introducing exploitable vulnerabilities to ferroptosis. These concepts might be explored as a therapeutic strategy allowing for selective ferroptosis induction in high-risk neuroblastoma and potentially other MYCN-amplified entities.