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 of glutamatergic NMDA receptors alleviate depressed mood? New data1 suggest that a critical step is that this stabilises an adaptor protein, 14-3-3η, which decouples GABAB receptor signalling and influences the activity of the intracellular protein mTOR. The upshot is a change in synaptic structure that produces a therapeutic effect; the rather innocuously named 14-3-3η protein seems to be the essential link for fast-acting antidepressants. Formidable problems exist with using ketamine as a therapeutic option, including a very quick decay in effectiveness, as well as concerns about the intravenous administration of a compound that is an anaesthetic, a commonly misused recreational drug, and a pro-psychotic. However, an improved understanding of its mechanisms of action is essential in enhancing our knowledge of the neuropathology of depression, offering the potential for development of novel compounds circumventing some of these limiting factors.