The contribution of smoke inhalation to cyanide-attributed morbidity and mortality arguably surpasses all other sources of acute cyanide poisoning. Research establishes that cyanide exposure is: (1) to be expected in those exposed to smoke in closed-space fires; (2) cyanide poisoning is an important cause of incapacitation and death in smoke-inhalation victims; and (3) that cyanide can act independently of, and perhaps synergistically with, carbon monoxide to cause morbidity and mortality. Effective prehospital management of smoke inhalation-associated cyanide poisoning is inhibited by: (1) a lack of awareness of fire smoke as an important cause of cyanide toxicity; (2) the absence of a rapidly returnable diagnostic test to facilitate its recognition; and (3) in the United States, the current unavailability of a cyanide antidote that can be used empirically with confidence outside of hospitals. Addressing the challenges of the prehospital management of smoke inhalation-associated cyanide poisoning entails: (1) enhancing the awareness of the problem among prehospital responders; (2) improving the ability to recognize cyanide poisoning on the basis of signs and symptoms; and (3) expanding the treatment options that are useful in the prehospital setting.