Inflammatory demyelinating diseases of the central nervous system (CNS) occur throughout the world and are the leading cause of nontraumatic neurological disability in young adults. They represent a broad spectrum of disorders that vary in their clinical course, regional distribution, and pathology. However, there can be a considerable overlap between at least some of these disorders, leading to misdiagnoses or diagnostic uncertainty. Multiple sclerosis (MS), the most common inflammatory demyelinating CNS disease affecting approximately one million adults, shares the basic pathological hallmark of CNS inflammatory demyelination. Advances based on recent systematic clinicopathologic-serologic correlative approaches have led to novel insights with respect to the classification of this disorder, the pathologic substrate of disability, a better understanding of the underlying pathogenic mechanisms involved in lesion formation, as well as the clinical relevance of cortical demyelination and normal appearing white matter pathology. In addition to prototypic MS, these diseases include Marburg variant of acute MS, Balo's concentric sclerosis, neuromyelitis optica, acute disseminated encephalomyelitis, and tumefactive MS. The last decade has seen a resurgence of interest in examining the lesions of these inflammatory demyelinating CNS disorders with newer and more sophisticated immunological and molecular tools. Herein, we review the clinicopathologic features of these CNS inflammatory demyelinating disorders and discuss recent advances in understanding their immunopathogenesis.