The article reviews the biochemistry and pathology of radical-mediated protein oxidation. Radical-mediated damage to proteins can be initiated by electron leakage, metal-ion-dependent reactions, and autoxidation of lipids and sugars. The resulting protein oxidation is O2-dependent and involves several propagating radicals, such as alkoxy radicals. The products of protein oxidation include reactive species and stable products, with the chemistry of the latter being actively studied. Protein hydroperoxides can generate further radical fluxes upon reaction with transition-metal ions, while protein-bound reductants can reduce these ions and facilitate their reaction with hydroperoxides. Aldehydes may participate in Schiff-base formation and other reactions. Cells can detoxify some reactive species, such as reducing protein hydroperoxides to unreactive hydroxides. Oxidized proteins are often functionally inactive and their unfolding increases their susceptibility to proteases. However, certain oxidized proteins are poorly handled by cells, leading to their accumulation and damaging actions during aging and in pathologies like diabetes, atherosclerosis, and neurodegenerative diseases. Protein oxidation also plays a role in cellular remodeling and cell growth, and may sometimes serve as a protective mechanism. The review covers the sources of radicals, the chemistry of protein oxidation, and the mechanisms of reversal of oxidative lesions, including the involvement of thiol groups, methionine, Schiff bases, and protein unfolding. It also discusses protein fragmentation and polymerization, as well as the measurement and features of radical-mediated protein fragmentation and polymerization. The article further explores protein oxidation in solution, membranes, and lipoproteins, and the enzymic removal of oxidized proteins.The article reviews the biochemistry and pathology of radical-mediated protein oxidation. Radical-mediated damage to proteins can be initiated by electron leakage, metal-ion-dependent reactions, and autoxidation of lipids and sugars. The resulting protein oxidation is O2-dependent and involves several propagating radicals, such as alkoxy radicals. The products of protein oxidation include reactive species and stable products, with the chemistry of the latter being actively studied. Protein hydroperoxides can generate further radical fluxes upon reaction with transition-metal ions, while protein-bound reductants can reduce these ions and facilitate their reaction with hydroperoxides. Aldehydes may participate in Schiff-base formation and other reactions. Cells can detoxify some reactive species, such as reducing protein hydroperoxides to unreactive hydroxides. Oxidized proteins are often functionally inactive and their unfolding increases their susceptibility to proteases. However, certain oxidized proteins are poorly handled by cells, leading to their accumulation and damaging actions during aging and in pathologies like diabetes, atherosclerosis, and neurodegenerative diseases. Protein oxidation also plays a role in cellular remodeling and cell growth, and may sometimes serve as a protective mechanism. The review covers the sources of radicals, the chemistry of protein oxidation, and the mechanisms of reversal of oxidative lesions, including the involvement of thiol groups, methionine, Schiff bases, and protein unfolding. It also discusses protein fragmentation and polymerization, as well as the measurement and features of radical-mediated protein fragmentation and polymerization. The article further explores protein oxidation in solution, membranes, and lipoproteins, and the enzymic removal of oxidized proteins.