:Experimental autoimmune encephalomyelitis is a CD4+ T cell-mediated demyelinating disease of the CNS that serves as a model for multiple sclerosis. Cytokines and chemokines shape Th1 and Th17 effector responses as well as regulate migration of leukocytes to the CNS during disease. The CNS cellular infiltrate consists of Ag-specific and nonspecific CD4+ and CD8+ T cells, neutrophils, B cells, monocytes, macrophages, and dendritic cells. The mechanism of immune-mediated inflammation in experimental autoimmune encephalomyelitis has been extensively studied in an effort to develop therapeutic modalities for multiple sclerosis and, indeed, has provided insight in modern drug discovery. The present Brief Review highlights critical pathogenic aspects of cytokines and chemokines involved in generation of effector T cell responses and migration of inflammatory cells to the CNS. Select cytokines and chemokines are certainly important in the regulatory response, which involves T regulatory, B regulatory, and myeloid-derived suppressor cells. However, that discussion is beyond the scope of this brief review.