Dendritic cells (DCs) are essential antigen-presenting cells responsible for initiating cellular immune responses. The increasing interest in the mechanisms of DC trafficking has created new and exciting opportunities for bench-to-bedside therapies to treat autoimmune diseases of the central nervous system (CNS). However, tracking the migration of DCs in the CNS has proved to be more problematic owing to their low number in the immunologically privileged environment of the brain and high diversity as a cell population. A significant contributor to immune privilege in the brain is the blood-brain barrier, a unique structure recognized to regulate the entry of immune cells into the brain. Currently, it is hypothesized that the migration of DCs across the blood-brain barrier is critically important for the initiation of immune responses of CNS autoimmunity. This review summarizes the present knowledge on DC trafficking in the CNS and the main functions of these cells in initiating CNS autoimmunity. Selective identification of regulatory molecules and novel therapies to inhibit DC migration and function during CNS autoimmune diseases without affecting normal DC function under physiological conditions will be critical in treatments for neurological inflammatory diseases. © 2007 Future Medicine Ltd.