Autologous haematopoietic stem cell transplantation shows increasing promise as a therapeutic option for patients with treatment-refractory autoimmune disease, particularly systemic sclerosis and multiple sclerosis. However, this intensive chemotherapy-based procedure is not always possible due to potential treatment toxicities and comorbidities. The biological mechanisms of how this procedure induces long-term remission in autoimmune disease are increasingly understood. The focus of this review is on recent research findings on the role of CD4+ T regulatory cells (Tregs) in resetting the immune system leading to the eradication of the autoimmune disease after transplantation. Discovery of the precise mechanisms of this process will allow development of novel Treg-based therapies and thus avoid the need for intensive chemotherapy-based treatment for these autoimmune diseases in the future.