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The central nervous system (CNS) constitutes a tightly regulated milieu, where immune responses are strictly controlled to prevent neurological damage. This poses considerable challenges to the therapeutic management of CNS pathologies, such as autoimmune disorders and cancer. Tertiary lymphoid structures (TLS) are ectopic, lymph node-like structures containing B- and T-cells, often associated with chronic inflammation or cancer, which have been shown to be detrimental in autoimmunity but beneficial in cancer. In-depth studies of TLS induction in CNS disorders, as well as their precise role in regulating adaptive immune responses in this context, will be paramount to the development of novel TLS-targeting therapies. In the present chapter, we review the anatomical and physiological peculiarities shaping TLS formation in the CNS, their relevance in autoimmunity and cancer, as well as their implications for the development of novel therapeutic modalities for these patients., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)