Effectiveness of phenolic antioxidants in protecting against oxidative stress depends on their reactivity towards reactive oxygen species and the reactivity of the antioxidant phenoxyl radicals towards critical biomolecules. Reduction of phenoxyl radicals by intracellular reductant (ascorbate, thiols) as well as by enzymes or intermediates of electron transport (e.g., in mitochondria and the endoplasmic reticulum) recycles phenolic antioxidants, thus enhancing antioxidant protection. Several cascades may be involved in physiologically relevant recycling of vitamin E from its phenoxyl radicals. The two major ones are dihydrolipoic acid-->(GSH)-->ascorbate, and enzymes of electron transport-->coenzyme Q. Importantly, phenoxyl radicals of vitamin E are not directly reduced by intracellular thiols. By contrast, a number of natural phenolic compounds that act as very effective scavengers of reactive oxygen species and organic radicals, may generate reactive secondary radicals of antioxidants. These secondary radicals react and modify critical intracellular targets (lipids, proteins, and DNA). As a result, the role of these phenolic compounds as biological antioxidants may be limited because of their ability to cause cyto- and genotoxic effects. Typical examples are some estrogens and phenolic drugs (e.g., the antitumor drug, etoposide) that can protect lipids but oxidize GSH and protein sulfhydryls. Moreover, phenoxyl radicals produced in the course of radical scavenging by some phenolic compounds (e.g., phenol) are capable of oxidizing both proteins and lipids. Hence, reactivity of phenoxyl radicals should be considered as a critical factor in the development of new antioxidant protectants.