The anatomy of the Virchow-Robin space is reviewed and attention is drawn to its importance as a compartment which is in communication with lymphatic channels of the head and neck and in which local immunological reactions take place. Macrophages in the Virchow-Robin spaces express MHC class II antigens and are well placed to interact with lymphocytes derived from the blood in initiating and promoting immune response to foreign antigens in the brain. The immunological reactions taking place in the Virchow-Robin spaces in encephalitis, multiple sclerosis and human immunodeficiency virus encephalitis are examined for the light they may throw on the pathogenesis of these conditions.