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Cyanide is one of the oldest known poisons in human history. In the 1980s, seminal work began to elucidate the broad cellular mechanisms of cyanide toxicity beyond its canonical inhibition of cytochrome c oxidase. In the 1990s, endogenous metabolites were shown to sequester cyanide, and these became promising avenues for the development of a cyanide antidote. However, an FDA-approved metabolite-based cyanide antidote did not come to fruition. More recently, in the past 10 years, advances in mass spectrometry-based metabolomics profiling, subcellular drug targeting, and genome editing have brought fresh perspectives to the concept of a metabolism-based cyanide antidote. Here, we review the mechanisms of cyanide toxicity with a focus on intermediary metabolism. We discuss the current state of our knowledge and gaps in our understanding of the metabolic mechanisms that contribute to cyanide poisoning, in addition to highlighting recent findings that break new ground in the field. We present the theory of redirecting intermediary metabolism to counteract cyanide poisoning: while cyanide shifts metabolism from oxidative phosphorylation to glycolysis, the metabolome encompasses hundreds of pathways; thus, potential therapeutic opportunities may reside in activating metabolism into other pathways. Potential approaches to targeting metabolism as a therapeutic intervention for cyanide poisoning will also be discussed. These targets represent an opportunity for a significant paradigm shift from current FDA-approved treatments, which chelate the chemical toxicant but do not reverse the broad spectrum of cellular and metabolic damage caused by cyanide, to a treatment that may improve the long-term effects of cyanide poisoning.