Migraine headache and its associated symptoms have plagued humans for two millennia. It is manifest throughout the world, and affects more than 1/6 of the global population. It is the most common brain disorder, and is characterized by moderate to severe unilateral headache that is accompanied by vomiting, nausea, photophobia, phonophobia, and other hypersensitive symptoms of the senses. While there is still a clear lack of understanding of its neurophysiology, it is beginning to be understood, and it seems to suggest migraine is a disorder of brain sensory processing, characterized by a generalized neuronal hyperexcitability. The complex symptomatology of migraine indicates that multiple neuronal systems are involved, including brainstem and diencephalic systems, which function abnormally, resulting in premonitory symptoms, ultimately evolving to affect the dural trigeminovascular system, and the pain phase of migraine. The migraineur also seems to be particularly sensitive to fluctuations in homeostasis, such as sleep, feeding and stress, reflecting the abnormality of functioning in these brainstem and diencephalic systems. Implications for therapeutic development have grown out of our understanding of migraine neurophysiology, leading to major drug classes, such as triptans, calcitonin gene-related peptide receptor antagonists, and 5-HT1F receptor agonists, as well as neuromodulatory approaches, with the promise of more to come. The present review will discuss the current understanding of the neurophysiology of migraine, particularly migraine headache, and novel insights into the complex neural networks responsible for associated neurological symptoms, and how interaction of these networks with migraine pain pathways has implications for the development of novel therapeutics.