Ferroptosis is an iron-dependent cell-death modality driven by oxidative phospholipid damage. In contrast to apoptosis, which enables organisms to eliminate targeted cells purposefully at specific times, ferroptosis appears to be a vulnerability of cells that otherwise use high levels of polyunsaturated lipids to their advantage. Cells in this high polyunsaturated lipid state generally have safeguards that mitigate ferroptotic risk. Since its recognition, ferroptosis has been implicated in degenerative diseases in tissues including kidney and brain, and is a targetable vulnerability in multiple cancers-each likely characterized by the high polyunsaturated lipid state with insufficient or overwhelmed ferroptotic safeguards. In this Perspective, we present progress toward defining the essential roles and key mediators of lipid peroxidation and ferroptosis in disease contexts. Moreover, we discuss gaps in our understanding of ferroptosis and list key challenges that have thus far limited the full potential of targeting ferroptosis for improving human health.