There is mounting evidence indicating that brain-targeted autoimmunity develops in a large range of neurological conditions in which the involvement of the adaptive immune system was not previously envisioned. Beyond multiple sclerosis and a few central nervous system (CNS) disorders acknowledged to be autoimmune by nature, it now appears that multiple neurological conditions are accompanied by brain-targeted autoimmune processes. The eleven articles gathered in this Research Topic fall into four main research themes, which represent the likely focus of major investigative efforts in the near future: i) links between physiological and pathological brain-targeted autoimmunity, ii) the functional impact of post-lesional brain-targeted autoimmunity, iii) the role of brain-targeted autoimmunity in neurodevelopmental and neurodegenerative disorders, iv) the emergence of new clinical entities associated with brain-targeted autoimmunity. In this editorial, we first provide a brief summary of the main advances presented by these articles. We then discuss the concept of “brain-targeted autoimmunity” and how to refine it in order to improve our pathophysiological understanding of a growing array of CNS diseases.