Five categories of reaction of the Escherichia coli R2 protein of ribonucleotide reductase (RNR) are defined from mechanistic studies with hydroxyurea, methylhydroxylamine, hydroxamic acid derivatives, long-lived organic radicals of which methyl viologen MV+ is a good example, hydrazine, catechol and their derivatives. Attention is focused on whether a particular reagent reduces only the tyrosyl radical (Tyr.) giving metR2, or the Tyr. and Fe(III)2 in consecutive steps to give fully reduced R2. In the case of hydrazine (N2H4), reduction of both the Tyr and Fe(III)2 occurs in a uniphasic process, while with di-imide (N2H2) it has already been demonstrated that the Tyr. is reduced and that Fe(II)Fe(III) semi-metR2 is formed. A further mechanism is observed with catechol and catechol-like derivatives (in this work Didox), in which there is reduction of the Tyr. in the first stage, followed by scavenging of the Fe(III) in the second. The latter offers a more permanent inactivation of R2, meriting more extensive study in the context of cancer drug therapy. Comparative studies on mouse R2 suggest that the Tyr. and Fe(III)2 of mammalian R2 forms may be more exposed, and as compared to E. coli R2 are approximately an order of magnitude more reactive.