Purpose of Review Neuromyelitis optica (NMO) classically features a clinical presentation that includes longitudinally extensive transverse myelitis and optic neuritis. However, many other pathognomonic phenomena have more recently been described in patients diagnosed with NMO, including intractable hiccups, vomiting, and painful tonic spasms, but less has been reported regarding the relationship between NMO and headache. Though headache is well established as both a symptom and comorbidity of multiple sclerosis (MS), it has been much less described thus far in the NMO literature and warrants more careful evaluation. Many questions remain unanswered about the relationship between NMO and headache, including headache prevalence in certain groups, distribution of primary and symptomatic headache disorders that are seen most frequently and the specific neuroimaging findings that are associated with an increased risk of headache. Recent Findings Various types of headache, such as cervicogenic headache and trigeminal autonomic cephalalgia-like headache, have been reported as the initial clinical presentation of NMO. Other publications have emphasized the association of NMO and other etiologies of headache, such as trigeminal neuralgia, PRES, and preeclampsia. Certain MR imaging findings such as medullary lesions in patients with NMO have also been associated with headache. Summary The link between headache and NMO is evident not only in limited case reports and clinical studies but also with both MR imaging and even with some potential common underlying biomarkers such as pentraxin-3 and interleukin-6. Developing a further understanding in the association between these two diseases may lead to better management of headache in patients with NMO and potentially lead to earlier diagnosis of NMO in whom headache may serve as an initial presenting symptom and may even herald a disease exacerbation.