This review addresses current knowledge of the molecular trafficking signals involved in the migration of circulating leukocytes across the highly specialized blood–central nervous system (CNS) barriers during immunosurveillance and inflammation. In this regard, adhesion molecules and activating and chemotactic factors are also discussed and the regional variability in the brain and spinal cord parenchyma are also considered. Furthermore, direct passage into cerebrospinal fluid (CSF) is discussed, in the context of CNS immunosurveillance. The potential differences that characterize leukocyte entry into these varied anatomical sites are highlighted, with special emphasis on studies of the pathogenesis of multiple sclerosis and its animal models. An update on findings from clinical trials of natalizumab is also provided.