Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. Ferrostatin-1 (Fer-1) is a potent and selective inhibitor of ferroptosis, a form of nonapoptotic, iron-dependent, oxidative cell death. Fer-1 inhibits cell death in models of Huntington's disease (HD), periventricular leukomalacia (PVL), and kidney dysfunction. It inhibits lipid peroxidation but not mitochondrial reactive oxygen species (ROS) formation or lysosomal membrane permeability. A mechanistic model of Fer-1's activity was developed, leading to the creation of improved ferrostatins. These studies suggest numerous therapeutic applications for ferrostatins, with lipid peroxidation mediating diverse disease phenotypes. Fer-1 is an arylalkylamine that acts via a reductive mechanism to prevent membrane lipid damage and inhibit cell death. It is effective in preventing cell death in HD brain slices, PVL models, and kidney proximal tubule models. Fer-1 and its analogs, such as SRS11-92, inhibit cell death by preventing oxidative lipid destruction. Fer-1 inhibits the oxidative destruction of unsaturated fatty acids, as shown by metabolomic analysis. In yeast models, Fer-1 inhibits PUFA auto-oxidation-induced cell death. Fer-1's mechanism involves reducing lipid peroxides to alcohols or scavenging lipid radicals. A SAR study of Fer-1 analogs revealed that both secondary amines are essential for activity. Modifications to the Fer-1 scaffold, such as introducing heteroatoms or extending the ethyl ester, affected potency. Some analogs, like SRS11-92, were more potent than Fer-1. Fer-1 and its analogs also showed antioxidant activity in the DPPH assay, indicating their ability to quench free radicals. These findings suggest that ferrostatins are useful probes for studying ferroptosis and could lead to future therapies for lipid-peroxidation-mediated tissue injury in various diseases.Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. Ferrostatin-1 (Fer-1) is a potent and selective inhibitor of ferroptosis, a form of nonapoptotic, iron-dependent, oxidative cell death. Fer-1 inhibits cell death in models of Huntington's disease (HD), periventricular leukomalacia (PVL), and kidney dysfunction. It inhibits lipid peroxidation but not mitochondrial reactive oxygen species (ROS) formation or lysosomal membrane permeability. A mechanistic model of Fer-1's activity was developed, leading to the creation of improved ferrostatins. These studies suggest numerous therapeutic applications for ferrostatins, with lipid peroxidation mediating diverse disease phenotypes. Fer-1 is an arylalkylamine that acts via a reductive mechanism to prevent membrane lipid damage and inhibit cell death. It is effective in preventing cell death in HD brain slices, PVL models, and kidney proximal tubule models. Fer-1 and its analogs, such as SRS11-92, inhibit cell death by preventing oxidative lipid destruction. Fer-1 inhibits the oxidative destruction of unsaturated fatty acids, as shown by metabolomic analysis. In yeast models, Fer-1 inhibits PUFA auto-oxidation-induced cell death. Fer-1's mechanism involves reducing lipid peroxides to alcohols or scavenging lipid radicals. A SAR study of Fer-1 analogs revealed that both secondary amines are essential for activity. Modifications to the Fer-1 scaffold, such as introducing heteroatoms or extending the ethyl ester, affected potency. Some analogs, like SRS11-92, were more potent than Fer-1. Fer-1 and its analogs also showed antioxidant activity in the DPPH assay, indicating their ability to quench free radicals. These findings suggest that ferrostatins are useful probes for studying ferroptosis and could lead to future therapies for lipid-peroxidation-mediated tissue injury in various diseases.