Interleukin-2 (IL-2), the first cloned cytokine, is a multifunctional molecule with diverse cellular origins. As a pivotal T-cell growth factor, IL-2 is crucial for T-cell proliferation and the generation of effector and memory cells. Besides, IL-2 and its receptor (IL-2R) are expressed in various cell types within the brain and have been implicated in the pathogenesis of several neurological disorders. In conditions characterized by primary or secondary inflammatory processes, such as multiple sclerosis, Alzheimer's disease, ischemic stroke, and encephalitis, IL-2/IL-2R expression exhibits region- and subtype-specific and variations associated with disease stages in plasma, cerebrospinal fluid (CSF), and brain tissues. These variations highlight the potential of IL-2/IL-2R as promising diagnostic and prognostic biomarkers, as well as therapeutic targets. This review provides a comprehensive summary of the roles, expression patterns, and regulatory mechanisms of IL-2/IL-2R in immune-mediated disorders of the central nervous system (CNS), with particular emphasis on the impact of genetic polymorphisms in IL-2 and IL-2R subunits on disease susceptibility and progression. In addition, the research advances in IL-2/IL-2R-targeted therapies are also discussed, offering novel insights into the immunotherapeutic strategies for CNS diseases.Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.