The possibility that spreading depression (SD) of cortical activity, a phenomenon observed in all vertebrates, causes the aura of migraine remains an open question in spite of nearly half a century of investigation. SD is also thought to be associated with the progressive neuronal injury observed during cerebral ischaemia. Thus, the ability to detect and investigate SD in humans might prove clinically significant. Animal studies of cortical spreading depression (CSD) have benefited greatly from the advent of relatively non-invasive imaging techniques. The use of these new imaging techniques for clinical studies will accelerate progress in this area of neurobiology.