Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 24 5 2025 09 16 563 580 EN Mansur Aliyu Department of Immunology, School of Public Health, International Campus, Tehran University of Medical Sciences, Tehran, Iran Ali Saboor-Yaraghi Department of Immunology, School of Public Health, International Campus, Tehran University of Medical Sciences, Tehran, Iran Mohamad Ali Sahraian Multiple Sclerosis Research Centre, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran Farshid Noorbakhsh Department of Immunology, Tehran University of Medical Sciences, Tehran, Iran 2025 01 07 2025 06 02 Multiple sclerosis (MS) is a neuroinflammatory disorder that is characterized by demyelination, neurodegeneration, and immune dysregulation. The experimental autoimmune encephalomyelitis (EAE) model has helped to elucidate MS pathophysiology and test therapies. This review synthesizes current literature on the development, applications, and translational significance of EAE models in MS research. It discusses various EAE induction protocols, including active and passive immunization, and highlights advancements such as humanized mice and induced pluripotent stem cell (iPSC)-derived neuronal models. The review evaluates the role of EAE in identifying immune pathways, validating therapeutic agents like glatiramer acetate and natalizumab, and exploring precision medicine approaches through biomarker discovery. The EAE model replicated the key features of MS, including inflammation, demyelination, and axonal loss, facilitating therapy development. However, its predictive validity faces limitations, such as heterogeneity in disease induction, underrepresentation of chronic progression, and species differences. Innovations, such as humanized mouse models and iPSC-derived neurons, show promise in addressing these challenges. EAE research has advanced biomarker-based personalized treatments, although further validation is required. Despite its widespread use, EAE has limitations in terms of variability in disease induction, incomplete MS feature replication, species-specific responses, and clinical translation. Addressing these limitations remains crucial for therapeutic development, focusing on analyzing model limitations and strategies to overcome translational barriers. This review offers immunologists a comprehensive overview of EAE's contributions of EAE to MS research and its potential to inform the development of novel therapeutic approaches for this debilitating disease. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/4301 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/4301/2206