There is now evidence that high-dose immune ablation and autologous hematopoietic stem cell transplantation in humans triggers a reconstitution program that leads to the comprehensive renewal of the T cell repertoire. We argue here that several features of this program help to explain how autologous hematopoietic stem cell transplantation can induce long-term clinical remission from organ-specific-, as well as systemic, autoimmune diseases. We propose a model envisioning a coordinated sequence of events, rebuilding an immune system that is competent against infection but that is substantially reconfigured in a way that is less likely to redevelop autoimmunity.