Hypothalamic deep brain stimulation (DBS) has been used for more than a decade to treat cluster headache (CH) but its mechanisms remain poorly understood. The authors have successfully treated a patient with CH using hypothalamic DBS and found that the contact used for chronic stimulation was located in a white matter region posterior to the mammillary bodies. Fiber tracts crossing that region were the medial forebrain bundle and those interconnecting the hypothalamus and brainstem, including the dorsal longitudinal fasciculus. Because the stimulation of axons is an important mechanism of DBS, some of its clinical effects in CH may be related to the stimulation of fibers interconnecting the hypothalamus and brainstem.