The role of T regulatory (Treg) cells expressing the forkhead box transcription factor 3 (foxp3) in the control of autoaggressive immune responses is the subject of intense investigation. Here we explore the contribution of these cells to the regulation of experimental autoimmune encephalomyelitis (EAE). Starting from a historical perspective, we review their roles in preventing spontaneous disease, in setting the threshold for activation of a pathogenic response and in critically mediating the natural recovery from EAE. Current uncertainties and controversies are discussed in regard to EAE and multiple sclerosis as well as the potential for Treg-targeted immunotherapy. (C) 2007 Elsevier B.V. All rights reserved.