Research groups have identified several factors contributing to protection of cellular DNA against ionizing radiation-induced DNA strand damage. These factors include (a) scavenging of hydroxyl radicals produced, during radiolysis of water, by histones and soluble nuclear components, (b) quenching of DNA radicals by proteins and non-protein thiols, and (c) reduced overall accessibility of hydroxyl radicals to DNA as a consequence of DNA compaction induced by histones and divalent or polyvalent cations. Cell-free in vitro systems are useful for evaluating the effectiveness of radioprotective drugs in order to investigate underlying mechanisms of protection. In this article, we review some of our recent studies on the radiation protection of a model plasmid DNA by metal ions, by natural polyamines, by the aminothiol WR-1065 (metabolite of the well-known radioprotective drug Ethyol or WR-2721) and by the symmetrical disulfides WR-33278 and WR-25595501 (metabolites of WR-2721 and WR-151327, respectively). Additionally, we examine the effect of the WR disulfides on the ⁶⁰Co-radiolysis of DNA alkylated by the nitrogen mustard mechlorethamine. This article also addresses relevant published findings of other researchers in this general area of research. We stress here the role played by a ligand-induced conformational change, the packaging of DNA in condensed structures, in the radioprotection by highly charged ions or molecules. Many similarities as well as differences exist between photodamaged and radiodamaged DNA. This review will be of use to both radiobiologists, and photobiologists seeking to better understand the mechanisms involved in radiation protection and repair.