The cause of multiple sclerosis is generally considered to be entirely T cell mediated. However, recent reports of studies in a variety of animal models of inflammatory demyelinating disease, coupled with detailed pathological analysis and neuroimaging studies of multiple sclerosis patients, indicate that the events involved in the formation of the multiple sclerosis lesion may be more complicated. This complex pathogenesis is reflected in the variable response of multiple sclerosis patients to immunomodulatory therapy.