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The onset of cluster headache pain seems to be related to the activation of a nerve pathway at the base of the brain, called the trigeminal-autonomic reflex pathway. Activation of the trigeminal nerve stimulates nearby related nerves that cause eye tearing and nasal congestion as well as other autonomic symptoms. The hypothalamus, for unknown reasons, appears to cause stimulation and activation of the trigeminal nerve which is the basis for the excruciating pain that ensues in a cluster headache attack.

Thus, it seems clear that the trigger for cluster headache is in the hypothalamus and that the vascular changes (e.g., increased blood flow of the internal carotid artery, dilation of the ophthalmic artery), are related to the headache but not the cause. Thus cluster headaches are now considered to be "neurovascular" headaches. Cluster headaches are not caused by tumors or aneurysms, although lesions of the brain may present as cluster-like headaches. It is recommended that all individuals with cluster headache should have an MRI of the brain and an MR angiogram looking at the blood vessels in the brain and neck. Some researchers regard cluster headache as a hypothalamic syndrome in which the involvement of vascular and trigeminal nerve pathways may reflect secondary involvement, rather than as a particular type of headache with specific symptoms.