Cluster headache (CH) is characterised by unilateral pain and ipsilateral autonomic features. To date, no molecular genetic evidence has been shown for CH. Small pedigrees and low penetrance render the identification of the CH-gene quite difficult. Nonetheless the association of CH and migraine to a new class of amine, namely trace or elusive amines such as tyramine, octopamine and synephrine, has recently been demonstrated. In particular, in comparison to healthy control subjects, all these neurotransmitters have been found to be greatly elevated in CH sufferers in plasma and platelets both in active and remission periods. A cluster of gene-encoding G-protein-coupled receptors that bind and are activated by trace amines was identified in the long arm of chromosome 6q23. We evaluated two families with CH by linkage analysis to 6q23 region and the mutation scanning of the TAR 1, TAR 3, TAR 4, TAR 5, PNR and GPR58 genes by denaturing high liquid chromatography is in progress in 16 familial cases.