In view of disease heterogeneity of multiple sclerosis and limited access to ex vivo specimens, different approaches must be undertaken to better understand disease pathogenesis and new therapeutic challenges. Here, we critically discuss models of experimental autoimmune encephalomyelitis (EAE) that reproduce specific features of the histopathology and neurobiology of multiple sclerosis and their shortcomings as tools to investigate emerging therapeutic approaches. By using EAE models we have understood mechanisms of T-cell mediated immune damage of the CNS, and the associated effector cascade of innate immunity. Also, the importance of humoral components of the immune system for demyelination has been delineated in EAE, before it was applied therapeutically to subtypes of multiple sclerosis. Yet, similar to multiple sclerosis, EAE is also heterogeneous and influenced by the selected autoantigen, species and the genetic background. In particular, the relevance of cytotoxic CD8 T cells for human multiple sclerosis has been underestimated in most EAE models, and no EAE model exists that mimics primary progressive disease courses of multiple sclerosis. Seventy years after the first description of EAE and the publication of >7000 articles, we are aware of the obvious limitations of EAE as a model of multiple sclerosis, but feel strongly that when used appropriately it will continue to provide a crucial tool for improving our understanding and treatment of this devastating disease.