The pathogenesis of medication overuse headache is unclear. Clinical and preclinical studies have consistently demonstrated increased excitability of neurons in the cerebral cortex and trigeminal system after medication overuse. Cortical hyperexcitability may facilitate the development of cortical spreading depression, while increased excitability of trigeminal neurons may facilitate the process of peripheral and central sensitization. These changes may be secondary to the derangement of central, probably serotonin (5-HT)-, and perhaps endocannabinoid-dependent or other, modulating systems. Increased expression of excitatory cortical 5-HT2A receptors may increase the susceptibility to developing cortical spreading depression, an analog of migraine aura. A reduction of diffuse noxious inhibitory controls may facilitate the process of central sensitization, activate the nociceptive facilitating system, or promote similar molecular mechanisms to those involved in kindling. Low 5-HT levels also increase the expression and release of calcitonin gene-related peptide from the trigeminal ganglion and sensitize trigeminal nociceptors. Thus, derangement of central modulation of the trigeminal system as a result of chronic medication use may increase sensitivity to pain perception and foster or reinforce medication overuse headache.