Cyanide is a potent and rapidly lethal poison whose clinical and laboratory diagnosis is difficult. Cyanide is released in fire settings involving wool, silk and many synthetic polymers posing a definite risk. Interactions of carbon monoxide released in a fire and cyanide have important physiological consequences. Although the classic mechanisms for the toxicology and antagonism of cyanide have been studied for many years, recent studies have cast doubt as to the mechanism of some of these antagonists. In the fire setting it is not clinically acceptable to administer nitrites to create methemoglobinemia. Cobalt salts are currently too toxic. Oxygen should be administered but there is no proven benefit of hyperbaric oxygen. Oxygen, thiosulfate and hydroxycobalamin are probably the best and safest currently available antidotes to manage this difficult setting. In the future, encapsulated rhodanese enzyme may provide additional rapid therapeutic intervention. It is anticipated that oxygen, thiosulfate and hydroxycobalamin are a safer and more clinically acceptable antidotal combination in the management of cyanide exposure in the fire setting. Our current understanding of combustion toxicology should provide an opportunity to remove building materials and furnishings which pose a cyanide hazard in a fire setting.