This article focuses on the distinct role of chemokines and chemokine receptors during CNS inflammation in experimental autoimmune encephalomyelitis (EAE) as an animal model for multiple sclerosis (MS). We review the evidence that chemokines and chemokine receptors have an intrinsic role in regulating and amplifying the inflammatory reactions in EAE or MS leading to disease outcome. A variety of studies examining temporal chemokine expression patterns, using chemokine and chemokine receptor knockout mice as well as administering passive anti-chemokine antibodies indicates that these molecules are critical regulatory components for leukocyte recruitment and/or leukocyte retention in the CNS. Therefore, chemokine and chemokine receptor expression is tightly interrelated to composition of inflammatory cells in CNS lesions and the onset of clinical diseases and provide viable targets for therapeutic intervention.