Cluster headache (CH) is a neurovascular headache disease characterized by recurrent, strictly unilateral, severe pain attacks. Despite its typical clinical features, including circadian rhythm of the attacks and ipsilateral autonomic dysfunction, the underlying pathophysiology of CH is still unclear. Electrophysiological data point to central disinhibition of the trigeminal nociceptive system as one of the key mechanisms of CH pain. Therefore, altered habituation pattern and changes within trigeminal-facial neuronal circuits due to central sensitization seem to be involved. One biochemical correlate is probably represented in dysfunctions of serotonergic raphe nuclei-hypothalamic pathways. Structural and functional imaging data show an alteration of hypothalamic structures in CH patients, supporting the hypothesis that the hypothalamus, according to its function as a circadian pacemaker, plays a pivotal role in CH pathology. Cortical and brainstem reflexes are reviewed to illuminate the pathophysiology of CH.