A number of oxime reactivators have been synthesized and studied for the antidotal treatment of poisoning by toxic organophosphorus agents, and several oximes are currently available to reactivate the organophosphorus agents-induced acetylcholinesterase inhibition. However, there is no oxime with broad spectrum suitable for the antidotal treatment of poisoning with various organoposphorus warfare agents as well as insecticides. In addition, current available oximes have very limited brain-blood barrier (BBB) penetration, even though hydrophobic toxic organophosphorus agents can easily penetrate BBB. Therefore, the development of BBB permeable oxime reactivators is one of great challenges in these days. In this review, we summarize advances in the synthesis and reactivation evaluation of oximes that have been studied in our research group. Various approaches have been employed to design these analogs; for example, bispyridinium oximes with (CH2)2O(CH2)2 linkers, (CH2)O(CH2)nO(CH2) linkers and (CH2)n linkers as well as fluorinated bis-pyridinium oximes.