This review article by Stadtman and Levine discusses the mechanisms of reactive oxygen species (ROS)-mediated oxidation of proteins and free amino acids. The studies have revealed that oxidation can lead to various modifications, including hydroxylation, nitration, nitrosylation, sulfoxidation, chlorination, and the formation of carbonyl derivatives. Oxidation can also result in the cleavage of peptide bonds and the formation of cross-linked protein aggregates. The accumulation of oxidized proteins is influenced by ROS formation rates, antioxidant levels, and proteolytic activity, and it is a marker of oxidative damage. Surface-exposed methionine and cysteine residues are particularly sensitive to oxidation but are reversible. The article also highlights the role of metal-catalyzed oxidation in site-specific modifications, such as the conversion of lysine, arginine, and proline residues to carbonyl derivatives. These mechanisms are crucial for understanding the aging process and age-related diseases.This review article by Stadtman and Levine discusses the mechanisms of reactive oxygen species (ROS)-mediated oxidation of proteins and free amino acids. The studies have revealed that oxidation can lead to various modifications, including hydroxylation, nitration, nitrosylation, sulfoxidation, chlorination, and the formation of carbonyl derivatives. Oxidation can also result in the cleavage of peptide bonds and the formation of cross-linked protein aggregates. The accumulation of oxidized proteins is influenced by ROS formation rates, antioxidant levels, and proteolytic activity, and it is a marker of oxidative damage. Surface-exposed methionine and cysteine residues are particularly sensitive to oxidation but are reversible. The article also highlights the role of metal-catalyzed oxidation in site-specific modifications, such as the conversion of lysine, arginine, and proline residues to carbonyl derivatives. These mechanisms are crucial for understanding the aging process and age-related diseases.