During the last decade, numerous studies have been carried out to explore the function of the immune system in cluster headache and the release of reciprocal informational molecules from pain-sensitive structures. These neuroimmunological findings in cluster headache syndrome, although carefully considered, have varied from genetic aspects (HLA antigens) to functional activity of the immune system (NK cytotoxicity), and from study of the receptor expression of classical neurotransmitters of pain (5-HT, histamine) on immunocompetent cells, to the study of cytokines with a potent pro-inflammatory activity (interleukin-1). Other aspects considered have ranged from the study of the effectiveness of substances possessing a wellknown activity on the immune system (prednisone, lithium carbonate) in shortening cluster attacks to the 5-HT receptor expression changes observed on a peripheral substrate (monocytes) after the administration of sumatriptan. Although this was an exciting area of pioneering research, we have always interpreted our findings cautiously. In summary, we now believe that the neuroimmunological aspects of cluster headache can be proposed as an integrative model and that this immunological mechanism could improve our understanding of the pathogenic basis for this still obscure disease.