Substantial evidence supports autoimmune activity as the etiologic mechanism underlying multiple sclerosis (MS). Both the innate and the adaptive arms of the immune system are involved in the aberrant response to several antigens associated with the myelin sheath and oligodendrocytes (OGCs) after the activation of immune cells by self- or cross-reactive microbial pathogens. The CD4(+) Th1 cell, in particular, has been implicated, but it is abetted by a variety of other cell types (CD8(+) cells, B cells, macrophages, and microglia) and soluble products (proteases, cytokines, and nitric oxide [NO]) that act both outside of and within the CNS. This review describes recent and salient findings from animal models and human clinical studies that have established our current understanding of the distinct steps in the development of immune autoreactivity that culminates in the CNS lesions associated with MS.