This chapter reviews the growing clinical and scientific literature regarding neuromyelitis optica (NMO) and Aquaporin (AQP)-4 autoimmunity, with the emphasis on recent studies in children. Most of the clinical, immunological, and pathological insights into NMO in recent years have emanated from the identification of the disease-specific NMO-IgG antibody and its antigenic target, AQP4. NMO was considered to require absence of clinical disease outside the optic nerve or spinal cord, although clinically silent brain lesions were recognized as common in NMO. Diagnostic criteria published in 1999 proposed negative brain MRI at onset as a supportive criterion to differentiate NMO from multiple sclerosis (MS). McKeon et al. described that the most common cerebrospinal fluid finding in NMO is a lymphocytic or neutrophil predominant leukocytosis and elevated protein. Treatment for NMO must include effective therapies for acute attacks as well as the use of chronic immunosuppressive treatments to prevent attacks and related disability.