Since a decade autologous stem cell transplantation (ASCT) is successfully performed to treat patients with severe autoimmune disease. However, the mechanism of action of this intervention remains largely unknown. Scarce data from animal studies and human clinical trials indicate that, besides extensive immune ablation, restoration of regulatory immune networks is of critical importance. This review focuses on the role of naturally occurring and induced regulatory T cells in controlling immune reconstitution and restoration of immune tolerance and in preventing relapses of disease following ASCT.