Cortical spreading depression (CSD) is associated with a dramatic failure of brain ion homeostasis as well as efflux of excitatory amino acids from nerve cells and increased energy metabolism. There is strong clinical and experimental evidence to suggest that CSD is involved in the mechanism of migraine. This paper will, based on the experience related to the detection of CSD in humans, discuss pitfalls and possible strategies for detection of CSD in man. Development of reliable methods for detection of CSD in humans will determine the extent to which the large body of experimental findings from animal studies of CSD can be applied to the investigation and treatment of human brain disease. The paper is based on the experience that has been gained from two decades of studies of CSD in relation to clinical neurological diseases.