The immune system is designed to recognize and eliminate foreign (non-self) antigens. At the same time, there are mechanisms protecting the organism from development of inappropriate immune responses that are harmful to ones own body (allergy, autoimmunity) and those that help to silence the inflammatory responses and allow their resolution. Tolerance to self-antigens is a result of central tolerance (negative selection) and various mechanisms of peripheral tolerance that include anatomical sequestration of self-antigens, deletion of peripheral autoreactive lymphocytes, the development of lymphocyte functional unresponsiveness and action of T regulatory (Treg) cells. This article summarizes current knowledge about mechanisms of immunological tolerance that protect from development of immune responses to self-antigens present in the central nervous system (CNS). Finally, it discusses the subject of skin-induced tolerance as demonstrated in an animal model of autoimmune disease of the CNS, experimental autoimmune encephalomyelitis (EAE). The potential clinical use of this approach to regulate disease will be discussed.