Naloxone, which reverses the effects of opioids, was synthesized in 1960, though the hunt for opioid antagonists began a half-century earlier. The history of this quest reveals how cultural and medical attitudes toward opioids have been marked by a polarization of discourse that belies a keen ambivalence. From 1915 to 1960, researchers were stymied in seeking a “pure” antidote to opioids, discovering instead numerous opioid molecules of mixed or paradoxical properties. At the same time, the quest for a dominant explanatory and therapeutic model for addiction was likewise unsettled. After naloxone’s discovery, new dichotomizing language arose in the “War on Drugs,” in increasingly divergent views between addiction medicine and palliative care, and in public debates about layperson naloxone access. Naloxone, one of the emblematic drugs of our time, highlights the ambivalence latent in public and biomedical discussions of opioids as agents of risk and relief.