<p>Demyelinating disorders such as multiple sclerosis and leukodystrophies are on the rise, posing substantial challenges due to their progressive nature and the current limitations of therapies that effectively restore lost myelin. Over the past decade, advancements in regenerative neuroscience, including cutting-edge stem cell therapies, advanced biomaterials and groundbreaking gene-editing technologies, offer promising avenues for remyelination, immunomodulation and neural repair. Yet, to successfully transition these innovations into clinical therapies, we need robust preclinical models that accurately reflect disease pathology and predict treatment efficacy. This Review offers a thorough overview of the preclinical models utilized in regenerative neurology for demyelinating diseases, highlighting the rapid progress in biomaterial and gene-editing research, which requires meticulous testing and validation in both in vitro and in vivo environments. We begin by explaining the pathophysiology of demyelination, then provide an exhaustive discussion on various preclinical models, including toxin-induced, autoimmune, genetic, viral-induced and large animal models. This is followed by an exploration of emerging regenerative strategies, from cell-based and pharmacological approaches to bioengineered techniques, and we conclude with an analysis of current challenges, translational barriers and future directions in the field. By synthesizing insights from multiple disciplines, this Review strives to engage a diverse audience eager to connect laboratory discoveries with clinical applications in regenerative neuroscience.</p>