Cyanide has been part of plant metabolism and defense mechanisms for millions of years. People have also been exposed to cyanide since ancient times, mostly through cyanogenic plants used for food. In modern times, cyanide became part of many industrial processes. With the introduction of CN-assisted gold mining and the use of CN as a pest control agent in the nineteenth century, it became industrially significant. Both acute and chronic poisoning have a detrimental effect on the organism, mainly the heart, and nervous system. The molecular basis of CN poisoning was intensively explored, and critical pathways were identified as early as the 1930s. These fundamental investigations resulted in three categories of antidotes: methemoglobin inducers, sulfur donors, and cobalt compounds. Methemoglobin/NO producers (e.g., sodium nitrite, amyl nitrite, and dimethyl aminophenol), sulfur donors (e.g., sodium thiosulfate), and direct binding agents (e.g., hydroxocobalamin and dicobalt edetate) are now used in CN treatments. A concerted effort is being made to investigate innovative antidotal systems and develop them for quick administration at the site of intoxication in mass casualty scenarios. Novel antidotes, formulations, and delivery systems are improving bioavailability and efficacy, paving the way for a new generation of superior CN countermeasures. Some of the new antidotes currently under research are: α-ketoglutarate, cobinamide, hydroxylamine, sulfanegen and dimethyl trisulfide.