Chemokines and their receptors are essential elements in leukocyte trafficking during health and disease. There are three (or more) distinct routes of leukocyte entry into the central nervous system (CNS), and molecular mechanisms of physiological and neuroinflammatory leukocyte recruitment to the CNS are slowly coming into view. Migration of immune cells into cerebrospinal fluid supports CNS immunosurveillance. Current knowledge of the trafficking determinants that direct the leukocyte recruitment in CNS pathology relies in large part on studies of multiple sclerosis and its models including experimental autoimmune encephalomyelitis. Overlapping molecular signals are responsible for the migration of specific cells into the CNS during pathological inflammation and host defense, raising challenges and opportunities for therapeutic manipulation.