Experimental autoimmune encephalomyelitis (EAE) is a useful model of acute demyelinating disease. Some forms of EAE reflect chronic demyelination with exacerbations and remissions characteristic of multiple sclerosis (MS). The chronic models of MS reflect many of the pathophysiologic steps in MS, including the role of certain adhesion molecules, the influence of T cells and antibodies reactive to components of the myelin sheath, the participation of metalloproteases in penetrating the blood–brain barrier, and the cytotoxic role of certain cytokines. One of the three therapies, approved in the United States, for treatment of multiple sclerosis was developed preclinically based on its success in treating various models of EAE. However, the role of certain cytokines in EAE is contradictory to what is seen when tried experimentally in MS. Recognition of the discrepancies between MS and its experimental models is critical in attempting to design rational therapies for demyelinating disease.