Oximes are acetylcholinesterase reactivators of use in poisoning with organophosphorus inhibitors of cholinesterase (OPIChE: (organophosphates and organophosphonates). Pralidoxime (1) and obidoxime (2) are clinically used as an adjunct to atropine in such exposure. Clinical experience with oximes is however disappointing. The paper reviews the available data concerning the ability of established and new oximes to reactivate cholinesterases inhibited by two differently substituted prototypical organophosphates: ethyl-paraoxon (3) and methyl-paraoxon (4). Reactivation ability is quantified in vitro via the IC50 shift curve. The slope of the shift curve (tg α) is used to quantify the magnitude of the protective effect (nM IC50 increase per microM reactivator). The ranking of reactivator potencies of the examined oximes determined with 4 as an inhibitor is essentially the same as the ranking obtained using 3 as an inhibitor. In the in vitro model used, the presence of ethyl vs. methyl substituents does not seem to significantly alter the in vitro ability of the examined oximes to reactivate the esterase. In vitro derived results were subsequently validated in vivo in rats using 3 and 4 as cholinesterase inhibitors and various oximes as reactivator. Mortality data were compared and hazards ratios calculated using Cox proportional hazards model. Overall the ability of the in vitro testing (tg α determinations) to predict in vivo performance of the oximes is limited.