The trigeminal nerve transmits headache pain from blood vessels of the pia mater and dura mater. Triggers for this pain are not well understood, but probably are multiple and largely chemical and develop within the brain parenchyma, the blood vessel wall, and the blood itself. These unknown triggers stimulate the trigeminovascular axons, causing pain and releasing vasoactive neuropeptides from perivascular axons. Released neuropeptides activate endothelial cells, mast cells, and platelets to then increase extracellular levels of amines, arachidonate metabolites, peptides, and ions. Hyperalgesia and prolongation of pain develop as a consequence, mediated by products from activated cells and injured tissue. Within postsynaptic brain stem neurons of the trigeminal nucleus caudalis, trigeminovascular activation stimulates the expression of an early immediate response gene c-fos. Both neurogenic inflammation and c-fos expression are blocked by sumatriptan and ergot alkaloids via prejunctional mechanisms involving putative 5-HT receptors closely related to the 5-HT1D subtype on trigeminovascular fibers. The mechanisms of action of sumatriptan and ergot alkaloids described herein are unrelated to the nature of the migraine trigger or to the contractile state of vascular smooth muscle.