This chapter focuses on demyelinating disorders of the central nervous system (CNS)—including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), acute disseminated encephalomyelitis (ADEM), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), as well as recognized variants. While there is overlap in the clinical and paraclinical manifestations of these conditions, they represent distinct entities, both from an etiologic and pathophysiologic perspective. Developing a nuanced approach when a demyelinating condition is suspected is therefore imperative to ensuring early diagnosis, avoiding misdiagnosis, and implementing disease-modifying therapy when appropriate. Questions pertaining to the diagnosis of MS are based on the 2017 McDonald Criteria. Revisions to these criteria were proposed in 2024 to increase diagnostic accuracy and earlier diagnosis by adding the optic nerve as a 5th anatomical location, incorporation of kappa free light chains in the cerebrospinal fluid and radiographic findings (central vein sign, paramagnetic rim lesions) to aide in supporting a diagnosis of MS, as well as eliminating the need to demonstrate dissemination in time. The finalized 2024 McDonald Criteria were not available at the time of writing this chapter. There are many areas of active research within the field of neuroimmunology, providing insights into the role of immune dysregulation and the contribution of genetic, epigenetic, and environmental factors to CNS demyelination. Recent advancements in biomarker development, promising remyelination strategies, and an exploration of precision medicine all have the potential to greatly improve the quality of life for individuals living with demyelinating and other neuroinflammatory diseases.