Proteins are major target for radicals and other oxidants when these are formed in both intra- and extracellular environments in vivo. Formation of lesions on proteins may be highly sensitive protein-based biomarkers for oxidative damage in mammalian systems. Oxidized proteins are often functionally inactive and their unfolding is associated with enhanced susceptibility to proteinases. ROS scavenging activities of intact proteins are weaker than those of misfolded proteins or equivalent concentrations of their constituent amino acids. Protein oxidation and enhanced proteolytic degradation, therefore, have been suggested to cause a net increase in ROS scavenging capacity. However, certain oxidized proteins are poorly handled by cells, and together with possible alterations in the rate of production of oxidized proteins, may contribute to the observed accumulation and damaging actions of oxidized proteins during ageing and in pathologies such as diabetes, arteriosclerosis and neurodegenerative diseases. Protein oxidation may play a controlling role in cellular remodelling and cell growth. There is some evidence that antioxidant supplementation may protect against protein oxidation, but additional controlled studies of antioxidant intake to evaluate the significance of dietary/pharmacological antioxidants in preventing physiological/pathological oxidative changes are needed.