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The number of intoxications from xenobiotics—natural or synthetic foreign chemicals, or substances given in higher doses than typically present in humans—has risen tremendously in the last decade, placing poisoning as the leading external cause of death in the United States. This epidemic has fostered the development of antidotal nanomedicines, which we call “nano-antidotes,” capable of efficiently neutralizing offending compounds in situ. Although prototype nano-antidotes have shown efficacy in proof-of-concept studies, the gap to clinical translation can only be filled if issues such as the clinical relevance of intoxication models and the safety profile of nano-antidotes are properly addressed. As the unmet medical needs in resuscitative care call for better treatments, this Perspective critically reviews the recent progress in antidotal medicine and emerging nanotechnologies.