This chapter reviews the evidence that challenges traditional and unproven notions which perpetuate the singular importance of constriction and dilation to the genesis of migraine pain. New data in experimental laboratory models suggest that migraine headache may develop primarily from metabolic/neurophysiological events (as yet unidentified) within the cortical mantle, or from a disturbance in those regions of brain which closely approximate the distribution of trigeminovascular fibers innervating meningeal blood vessels. Accordingly, this chapter will review the consequences of trigeminovascular activation to pain and meningeal inflammation, and will summarize emerging molecular and pharmacological data suggesting that ergot alkaloids and sumatriptan alleviate pain primarily via activation of pre-junctional 5-HT1 heteroreceptors residing on primary afferent trigeminovascular fibers.