Multiple sclerosis (MS) is an inflammatory disease of the human central nervous system (CNS) which develops predominantly in young adults with certain predisposing genetic characteristics, often following exposure to initiating environmental insult(s) including viral infections. The causes of MS remain elusive and no entire cure is in sight. However, it is well known that interactions between the immune system and the CNS play a central role in MS pathogenesis. Patients with MS generate CD4+ autoreactive T cells that at some point differentiate to Th1 phenotype cells, which are the major players in maintaining a continuous destructive immune response against brain and spinal cord antigens. Other significant participants in MS pathogenesis involved in the destruction of the target tissue are cerebral endothelial cells, CD8+ T cells, B cells, complement, autoantibodies, cytokines, and chemokines. The presence and interactions of all these participants further complicate the pathogenesis of MS, and make finding a cure for MS challenging. This chapter looks at the roles of these factors in the development of MS.