Free radicals are a normal feature of cellular oxygen metabolism. However, free radical-associated damage is an important factor in many pathological and toxicological processes. For a long time, lipid peroxidation, mediated by oxygen-derived free radicals, was probably the most extensively investigated process. From more recent studies, it has become evident that proteins are also the targets of free radicals, and this has important implication for their activity, unfolding, and degradation, as well as in cell functioning. After giving a brief overview of the key role of proteins in the overall antioxidant defense, this review examines their role as targets of oxidation reactions, taking into account the reactivity of amino acid residues and some of their oxidation products. In light of recent data, we then consider the specific role of sulfur-containing amino acids in protein degradation and their possible interplay with the reversal of limited oxidative lesions. The participation of proteins in the overall antioxidant defense is also discussed, specifically the role of metallothionein as an intracellular antioxidant and that of albumin as a circulating antioxidant.