The pathoetiology and pathophysiology of migraine are widely accepted as unknown. The current article overviews the wide array of data associated with the biological underpinnings of migraine and provides a framwork that integrates previously disparate bodies of data. The importance of alterations in stress- and pro-inflammatory cytokine- induced gut dysbiosis, especially butyrate production, is highlighted. This is linked to a decrease in the availability of melatonin, and a relative increase in the N-acetylserotonin/melatonin ratio, which has consequences for the increased glutamatergic excitatory transmission in migraine. It is proposed that suboptimal mitochondria functioning and metabolic regulation drive alterations in astrocytes and satellite glial cells that underpin the vasoregulatory and nociceptive changes in migraine. This provides a framework not only for classical migraine associated factors, such as calcitonin-gene related peptide and serotonin, but also for a developmental pathoetiology of migraine. A number of future research and treatment implications arise, including the clinical utilization of sodium butyrate and melatonin in the management of migraine.