For a long time, the most important inflammatory demyelinating diseases of the central nervous system (CNS), for example, multiple sclerosis (MS) and neuromyelitis optica (NMO), were extremely hard to differentiate, often with severe consequences for affected patients. This changed with the discovery of NMO‐immunoglobulin G (IgG), a specific autoantibody which was detected in the vast majority of NMO patients, and with the demonstration that this autoantibody targets aquaporin 4 (AQP4), a water channel found on astrocytes in the CNS. These findings paved the way for the generation of experimental models of NMO. This chapter will discuss the contribution of experimental models to NMO research and what key questions remain to be addressed.