Special K’ has had various connotations over the years, and with respect to depressive illness ketamine has most recently been mooted as a potential antidepressant. It is intriguing because of its almost immediate effects, and a pharmacology that has little connection with the predominant monoamine hypothesis. How does its blockade ofglutamatergic NMDA receptors alleviate depressed mood? New data1suggest that a critical step is that this stabilises an adaptor protein,14-3-3η, which decouples GABAB receptor signalling and influencesthe activity of the intracellular protein mTOR. The upshot is a change insynaptic structure that produces a therapeutic effect; the ratherinnocuously named 14-3-3η protein seems to be the essential link forfast-acting antidepressants. Formidable problems exist with using ketamineas a therapeutic option, including a very quick decay in effectiveness, aswell as concerns about the intravenous administration of a compound that isan anaesthetic, a commonly misused recreational drug, and a pro-psychotic.However, an improved understanding of its mechanisms of action is essentialin enhancing our knowledge of the neuropathology of depression, offering thepotential for development of novel compounds circumventing some of theselimiting factors.