Although CD8 T cells are key players in neuroinflammation, little is known about their trafficking cues into the central nervous system (CNS). We used a murine model of CNS autoimmunity to define the molecules involved in cytotoxic CD8 T‐cell migration into the CNS. Using a panel of mAbs, we here show that the α4β1‐integrin is essential for CD8 T‐cell interaction with CNS endothelium. We also investigated which α4β1‐integrin ligands expressed by endothelial cells are implicated. The blockade of VCAM‐1 did not protect against autoimmune encephalomyelitis, and only partly decreased the CD8⁺ T‐cell infiltration into the CNS. In addition, inhibition of junctional adhesion molecule‐B expressed by CNS endothelial cells also decreases CD8 T‐cell infiltration. CD8 T cells may use additional and possibly unidentified adhesion molecules to gain access to the CNS.