A book originating from an annual meeting of the Oxygen Society (Charleston, South Carolina, 1995) [7] and dedicated to Paul Hochstein in occasion of his retirement is entitled The Oxygen Paradox: the preface and some interesting articles define The Oxygen Paradox as the dual effects of oxygen, in a manner reminiscent of Fridovich’s article 20 years before in The American Scientist, Oxygen: Boon and Bane [14]. It is clear that in both instances an equilibrium is referred to and that this equilibrium is encompassed by, on the one hand, the production of oxygen-centered radicals (concept today extended to sulfur-, nitrogen-, and carbon-centered radicals) and, on the other hand, the effective removal of these species, as accomplished by disproportionation to less reactive (non radical) molecules, interception by small antioxidant molecules, or specific antioxidant enzymes. Our current view of cellular antioxidant defenses can be categorized into primary and secondary defense systems. The primary defenses consist of a variety of antioxidant enzymes (superoxide dismutases, catalase, glutathione peroxidases, etc.) and a broad range of small antioxidant molecules. Secondary defenses include proteolytic and lipolytic enzymes as well as the DNA repair systems. Of growing interest are the small antioxidant molecules (some of them vitamins), such as α-tocopherol, ascorbic acid, carotenoids, coenzyme Q, uric acid, vitamin A, melatonin, and aminoindoles. Also of physiological and/or pharmacological interest are small molecule antioxidants, such as flavonoids and polyphenols, those contained in herbal antioxidants, and α-lipoic acid. A comprehensive and authoritative treatise on the chemical, biological, and clinical aspects of natural antioxidants, providing an in-depth account of current knowledge on these naturally occurring compounds, was recently published [4]. Likewise, synthetic antioxidants are currently being developed as therapeutic agents against oxidative stress. Such compounds include, among others, derivatives of natural antioxidants (e.g., α-tocopherol analogs), phenolic antioxidants (such as Probucol and Nitecapone), 21 aminosteroids or lazaroids, sulfhydryl-containing compounds (thiazolidine, ebselen, dithiolethiones), and low-molecular weight mimics of superoxide dismutase [19]. Examples of tissuedirected α-tocopherol analogs are the water-soluble, quaternary ammonium tocopherol derivatives, which accumulate in heart tissue, and the 2,3-dihydrobenzofuran-5-ol derivatives, which penetrate brain tissue. These compounds have potential use as cardioprotectors and against cerebrovascular diseases, respectively [20].