Multiple sclerosis is an inflammatory demyelinating and neurodegenerative disorder of the central nervous system (CNS). The primary cause of the disease remains unknown, but an altered immune regulation with features of autoimmunity has generally been considered to play a critical role in the pathogenesis. Historically, lesion development has been attributed to activation of CD4 and CD8 T lymphocytes, B lymphocytes, and monocytes in the peripheral circulation and the migration of these cells through the blood–brain barrier to exert direct or indirect cytotoxic effects on myelin, oligodendrocytes and neuronal processes in the CNS. This broadly accepted concept was significantly influenced by the experimental autoimmune encephalitis (EAE) model, in which either immunization with myelin antigens or injection of a myelin antigen-specific T cell line into a recipient results in inflammatory demyelination in the CNS. More recent studies reveal that the loss of oligodendrocytes and neurons begins in the earliest stages of the disease and may not always be associated with blood-derived inflammatory cells. The pathology affects both the white and the gray matters and the clinical disability best correlates with the overall neurodegenerative process. These newer observations prompted several revisions of the classical concept of MS and facilitated a shift from using EAE to using other model systems. This chapter summarizes the classical and more contemporary concepts of MS, and provides methodologies for employing the cuprizone model for further explorations of the pathogenesis and treatment of the disease.