The International Programme on Chemical Safety (IPCS)—a cooperative program of the World Health Organization (WHO), the International Labour Organization (ILO), and the United Nations Environment Programme (UNEP)—designates cyanide a priority chemical in relation to the potential impact on human health and the environment. Like other IPCS priority chemicals, cyanide is highly toxic, is a transboundary safety concern, is a target for risk management in multiple countries, is produced in large quantities, has dispersive use, and poses a risk for human exposure (Table 1). Acute exposure to cyanide has caused significant morbidity and mortality in household and industrial accidents, as well as in suicides and attempted genocides, wars, and acts of terrorism. The most common, but perhaps least recognized source of cyanide in cases of acute poisoning is from smoke caused by fires. This review is the product of a collaboration among experts in prehospital emergency medicine, public health and safety, and disaster preparedness. Current understanding of the causes, consequences, and management of cyanide poisoning are described as a potential advancement in antidotal therapy that could transform the provision of prehospital care to cyanide-poisoned victims.