The clinical presentation of pain in patients with migraine showing spread and referral of pain throughout the trigeminal and cervical innervation territories accompanied by hyperalgesia and allodynia indicates a dynamic trigemino-cervical interaction. The physiologic mechanisms may be convergence of trigemino-cervical afferents and central sensitization of trigemino-cervical neurons leading to dynamic neuroplastic changes during migraine. This review highlights the clinical phenotype and mechanisms of how nociceptive input from neck structures of the upper cervical spine are integrated into the trigemino-cervical system. The nociceptive input into the spinal cord also is subject to a modulation by segmental mechanisms in the spinal cord and by inhibitory projections from brain stem structures such as the periaqueductal gray. The functional relevance of these basic mechanisms is discussed with reference to recent studies using neurostimulation of afferent nerves aiming at pain modulation in patients with migraine.