Of the sensory nervous system associated signal substances it is only calcitonin generelated peptide (CGRP) that is reliably associated with the degree of pain in the acute attacks of primary headaches. The treatment with triptans alleviates both the pain and the associated CGRP release, putatively via a presynaptic effect on the sensory nerves. The studies of opoids and other sensory neuropeptides are inconsistent and require further analysis. Initial positive data on endothelin and its receptors have turned out negative. Nitric oxide mechanisms are still debated both in terms of initiation of attacks and for the treatment.