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Ketamine has been in clinical use for over half a century, yet its precise mechanisms of action remain mysterious for the large part. Its hypnotic effects appear to be largely mediated by blockade of NMDA and HCN1 receptors, but cholinergic, aminergic, and opioid systems appear to play both a positive and negative modulatory role in both sedation and analgesia. Ketamine's effects in chronic pain, and as an antidepressant, far outlast the actual drug levels, and are probably mediated by a secondary increase in structural synaptic connectivity that is mediated by a neuronal response to the ketamine-induced hyper-glutamatergic state.