Under normal physiological conditions there is minimal entry of immune cells into the central nervous system (CNS) for the purpose of immune surveillance. During inflammation, however, extensive infiltration of immune cells can lead to the induction of CNS autoimmune disease, for example multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). The barriers that regulate cellular entry are the blood-brain barrier (BBB) within the CNS parenchyma, and the blood-cerebrospinal fluid (blood-CSF) barrier within the choroid plexus. Understanding how these barriers function to allow the passage of leukocytes from the periphery into the CNS for normal immune surveillance, and under inflammatory conditions, is vital for the development of novel therapeutics targeting immune cell migration in CNS diseases. Contributions from selectins, chemokines, integrins and matrix metalloproteinases allow the migration of leukocytes across the BBB and into the CNS parenchyma. In EAE and MS, the strict maintenance of this process is lost and a large influx of cells is seen. This review focuses on the role of these homing molecules, chemokines and enzymes in the entry of leukocytes into the CNS during inflammatory conditions. It concludes with a model of immune cell entry of the CNS, summarising the current knowledge in this area. Targeting specific molecules to prevent infiltration of inflammatory cells into the CNS could allow disease inhibition without compromising beneficial immune surveillance.