Clinical neurophysiology and neuroimaging are two non-invasive approaches used to investigate the pathophysiological basis of primary headaches, including cluster headache (CH) and other trigeminal autonomic cephalalgias (TACs). Modern neuroimaging has revolutionized our understanding of the pathophysiology of primary headaches, and of TACs in particular, focusing on a cerebrovascular dysfunction hypothesis toward a central triggering cause. The introduction of single-photon emission computed tomography (SPECT), positron emission tomography (PET), and voxel-based morphometry has allowed us new insights into mechanisms underlying TACs and occurring during peripheral and/or central neuromodulation. The specific activation of neural structures that is observed exclusively in migraine and in TACs supports the hypothesis that primary headaches are driven predominantly by central nervous system dysfunction, and this has important implications from a therapeutic perspective. Neurophysiological examinations are of little value in the clinical setting; however, most of these tools offer vast potential for exploring further the pathophysiology of primary headaches and the effects of pharmacological treatments Trigeminofacial reflexes, the nociceptive flexion reflex, and evoked potentials have been used in TACs to explore the functional state of brainstem and spinal structures involved in pain processing, contributing to our understanding of the pathophysiology of these primary headaches.