This issue of Psychological Medicine carries a number of papers on the neurobiology of major depression. Those acquainted with the field will recognize some familiar topics and while familiarity can be comforting, it can also raise a sense of unease; as the millennium approaches should we still be enquiring about the role of decreased serotonin and increased cortisol in the pathophysiology of depressive disorders?

In our defence we can maintain that there is, in fact good evidence that serotonin and cortisol are implicated in the biology of depression. Our failure to tie down exactly how they are involved in the manifestation of the depressive syndrome does not reflect their lack of importance but rather the problems we have in asking the right questions and the technical difficulties we have answering them. So how far do the papers in this issue take us into this difficult territory ?