The classic article by Domino et al. was the first clinical report and presented the first-in-human study of what would become the drug ketamine. Ketamine has become an analgesic, anesthetic, antidepressant, and drug of misuse. It remains today the only "dissociative anesthetic". It has challenged classical pharmacologic theory and drug development paradigms. The first report on CI-581 could never have envisioned the pharmacologic complexity or clinical utility of this molecule.