Neuropathic facial pain is notoriously difficult to treat, regardless of its origin and duration. Since the first reported sphenopalatine ganglion blockade by Sluder in 1908, this ganglion has assumed an important role among the structures targeted for the treatment of facial pain. Recent years have witnessed the rise of neuromodulation over ablative procedures, including the development of an implantable stimulation device specially designed for use in the pterygopalatine fossa. Sphenopalatine ganglion stimulation has been demonstrated as effective and safe for refractory cluster headache, today the major indication for this therapy, but increasing evidence shows that the effect on the autonomic system and cerebral circulation could justify an even wider use of sphenopalatine ganglion stimulation for other chronic headache syndromes and vascular diseases.