On the battlefields of Syria, many innocent civilians have been killed or injured by sarin poisoning. In Malaysia in February 2017, a North Korean man was assassinated with VX at Kuala Lumpur International Airport. In the face of such threats, a more effective antidote against organophosphonate acetylcholinesterase (AChE) inhibitors is needed, one that can freely penetrate into the central nervous system (CNS) through the blood-brain barrier (BBB). In the 1995 Tokyo subway sarin attack, which produced more than 6,000 victims, 2-pyridinealdoxime methiodide was the most commonly used antidote in hospitals, but it was unable to prevent CNS damage and no other oximes have been approved for use in Japan. Ultimately, 12 people died, and many victims had severe neurological injuries or sequelae. Although more than 25 years have passed since the incident, progress has been slow in the development of a new antidote that can penetrate the BBB, restore AChE activity in the CNS, and definitely prevent brain injury. From the perspectives of countering terrorism and protecting innocent people from nerve agent attacks, the search for nerve agent antidotes should be accelerated with the goals of improving both survival and quality of life. This review gives an overview of a series of our studies on the development of a new antidote since the Tokyo subway sarin attack and emphasizes that there is unfortunately still no promising antidote for saving the CNS in Japan.Copyright © 2020 Elsevier B.V. All rights reserved.