The interaction between lymphocytes and brain endothelium is a central pathogenetic event in CNS autoimmunity and, thus, represents an important focus of investigation. Chemokine binding through specific G protein-coupled receptors (GPCRs) on lymphocyte surface activates integrins and induces inside-out signaling and lymphocyte arrest in microcirculation under physiological and pathological conditions. The complexity emerged from the signaling networks controlling integrin activation and the differences observed in the adhesion mechanisms between leukocyte subtypes and between vascular districts, suggest that future therapies designed to interfere with signal transduction pathways involved in integrin-dependent adhesion may be useful in treating inflammatory diseases of the central nervous system (CNS).