One of the most bewildering aspects of antioxidants is that their excellent ill vitro activity cannot necessarily be translated into ill vivo effect. Through summarizing the recent progresses made in free radical chemistry and biology, this dichotomy is tentatively explained in terms of the heterogeneity of biological systems and the interactions between antioxidants and surrounding molecules ill vivo, which also has important implications for updating the current strategies for screening and designing antioxidant drugs. (c) 2007 Elsevier Inc. All rights reserved.