We know that antidepressants: get into the brain; need certain pharmacology properties; have acute and chronic neurochemical effects; influence neuronal circuitry underpinning mood; alter emotional processing; have biological actions comprising only a modest part of the overall therapeutic effect. We don't know: the specific pharmacological, neuronal, neuropsychological actions necessary or sufficient for efficacy; how these interact with non-specific and psychological factors; how to effectively sequence treatment based on pharmacology; how to predict who will benefit from which, or any, drug. Effective prescribing remains an art in which how treatment is carried out is as important as what drug is used.