The initiation of migraine may be a central or peripheral process. In favor of a peripheral process are the discovery of neuronal pathways from scalp to dura and meninges to cortex, the inhibition in rats of cortical activation by botulinum toxin via Transient Receptor Potential Vanilloid type 1 (TRPV1) and Transient Receptor Potential cation channel, subfamily A, member 1 (TRPA1) receptors, and the profoundly effective migraine prevention seen rapidly with anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mABs), which do not cross the blood–brain barrier and therefore have only initial peripheral effects. In favor of a central process are the activation of central neuromodulatory pathways and nuclei, specifically in the dorsal pons. The genesis of aura is activation of N-methyl-D-aspartate receptor (NMDA) glutamate receptors and cortical spreading depression (CSD). The ability to suppress CSD is associated with acute and preventive effects by drugs and neuromodulation devices, but whether this suppression alone is sufficient for either clinical effect is unresolved. Migraine pain is due to both meningeal vasodilation and neurogenic inflammation. Presynaptic release of CGRP, vasoactive intestinal peptide (VIP), substance P (SP), neurokinin A, and likely, pituitary adenylate cyclase activating polypeptide-38 (PACAP-38) results in these processes. Triptans and ergots prevent release of CGRP, reverse CGRP-induced vasodilation, and interfere with return of the pain signal from periphery to brainstem. Anti-CGRP drugs and biologics can terminate migraine acutely (gepants) or prevent migraine (monoclonal antibodies). A trigemino-parasympathetic or trigeminal autonomic reflex arc involves efferents from the superior salivatory nucleus (SSN) synapsing in the sphenopalatine ganglion (SPG), and then post-synaptic neurons proceeding to sinus, ocular, and nasal organs. Activation of this reflex, which involves VIP, results in sinus-like symptoms or cranial autonomic symptoms and signs in migraine, and nociceptive afferents return signals to the brain via the first division of the trigeminal nerve or ophthalmic nerve. The exit of parasympathetic efferents via the SPG allows for targeting of this ganglion for acute and preventive treatment of migraine via blocks, ablation, or neuromodulation.