Terrible, agonizing, wretched, sickening and unbearable--these are words frequently used by patients with neuromyelitis optica (NMO) to describe a very common symptom of their disease: pain. More than 80% of patients with NMO experience pain from this condition, which severely affects their quality of life. At present, there is no known therapy that produces satisfactory relief from NMO-associated pain. In fact, contemporary pain therapy is largely ineffective in these patients, suggesting that the mechanisms underlying pain in NMO differ substantially from those of other treatable causes of pain. Until now, the near-complete neglect of research into pain mechanisms in NMO has precluded rational pain therapy. In this Perspectives article, expertise from the fields of neuroimmunology, neurology and pain research is combined to explore, for the first time, the mechanisms underlying pain in patients with NMO, and to identify molecular and cellular targets for therapy.