The importance of natural autoantibodies reacting with self-antigens has long been neglected, as tolerance to self was believed to be primarily dependent on the deletion of autoreactive clones during ontogeny. However, it is now well established that autoreactive antibodies and B- and T-cells are present in healthy individuals. Research into the properties of natural autoantibodies and their role in immune homeostasis has been extensively investigated for a number of years. This information should lead towards the therapeutic exploitation of natural autoantibodies in the immunotherapy of autoimmune and inflammatory disorders.