A survey is made of protection by procedures carried out before irradiation; an attempt is made to examine the logical processes which lay behind the various experiments, rather than the experimental data itself. It is suggested that there has been a tendency for research workers in this field to be divided into separate schools. One began with the demonstration >50 yr ago, that the response of human skin to x rays could be diminished by the application of pressure by means of a vacuum cup, and culminated in the discovery in 1950 that induction of anoxia is an effective method of protecting rats against total-body irradiation. The second trend had its origin in the work of radiochemists in the 1930's that radiochemical reactions, which were brought about by the products of the radiolysis of water, could be modified by simple procedures such as dilution or addition of other solvents, and later discovery of similar effects in biological systems. The separation of these two trends has not been absolute, and other mechanisms of radioprotection have also been considered. The work of Bacq and the Liege School is considered in detail. The anoxia hypothesis is often referred to in the literature ofmore » chemical protection, but there appears to be confusion as to its exact nature and limits. Two mechanisms had been suggested which related chemical protection to anoxia: pharmacological effects in vivo, and simple chemical removal of oxygen in vitro. It has been postulated that some protective drugs produce partial anoxia in vivo to explain many of the observed results, and it has appeared reasonable to suggest that all drugs, including those of the sulfhydryl group, act via anoxia, at least as far as the protection of mammalian tissues is concerned. Careful examination of the arguments brought forward in support of the anoxia hypothesis (as applied to mammalian tissues) shows that they are not as conclusive as they once appeared to be. The reversal of cysteine protection by oxygen under pressure does not prove that cysteine causes anoxia; this result is also compatible with the theory that oxygen and the protective agent are competing for interaction with a damaged site. Even so, the anoxia theory has fared better than the radical scavenger theory in that the majority of pharmacologically active compounds probably act in this way in vivo, and it is wise to eliminate anoxia as a possible cause when a drug is given in such high doses as to cause death in unirradiated controls. Also, sulfhydryl compounds do remove oxygen from solution, and this removal probably provides the explanation of some results. Drugs of the cysteine-cysteamine group can cause anoxia in a mammal if given in high enough doses; thus, both the mechanisms relating sulfhydryl compounds and anoxia which were suggested do, in fact, operate, but it now appears that a third pathway, not related to anoxia, may be a vital one both in vivo and in vitro. In this third theory, the cysteinecysteamine group of agents act primarily by the formation of mixed disulfides with tissue proteins. This hypothesis is more limited than either of the two so far considered, in that it is restricted to this one class of protectors. Factors supporting this hypothesis are pointed out. It is concluded, with respect to the mechanism of action of chemical protectors in vivo, that the majority of the pharmacologically active drugs, such as the amines, act by bringing about a state of tissue hypoxia. The cysteinecysteamine- AET group, on the other hand, although they can cause anoxia in some systems, have a protective action which is not entirely attributable to anoxia, and which is most readily explained in terms of healing of damage in a target molecule. (BBB)« less