Considerable advances have been made in our understanding of the immunobiology of autoimmune disease and its treatment with hematopoietic cell transplantation (HCT). In autoimmune disorders, the reconstituted immune system following lymphoablation and autologous HCT yields qualitative changes in immune defects and modifications in adaptive immune responses. Seminal experiments in animals demonstrated that allogeneic or autologous HCT could prevent progression or reverse organ damage from inherited (genetic) or acquired (antigen induced) autoimmune diseases. Convincing animal and clinical data now show that after HCT, the immune system is normalized and "reset". Following autologous transplantation, this resetting occurs via repertoire replacement. It is currently being studied whether and to what extent suppression of inflammation after HCT is due to reregulation of function or due to the eradication of disease associated T and/or B cell populations. There are now a number of published clinical reports with sufficient follow-up for determinations of safety and efficacy of HCT for autoimmune diseases. On behalf of colleagues in the European League Against Rheumatism (EULAR) and the European Group for Blood and Marrow Transplantation (EBMT), we review the experience with more than 1000 transplants for autoimmune disease in Europe along with the three major multinational randomized trials in for systemic sclerosis (SSc, the ASTIS study), multiple sclerosis (MS, the ASTIMS study), and Crohn's disease (CD, the ASTIC study). Completed phase II studies in the USA of transplantation for severe SSc, SLE and MS yield promising results. For individuals with SSc, there is dramatic improvement/resolution of dermal fibrosis and stabilization/improvement of pulmonary dysfunction reported up to 8 years after lymphoablative conditioning and autologous HCT. Currently, randomized phase III studies are recruiting subjects in the USA with SSc, MS and CD. In addition, 9 other phase I and II trials in the USA are recruiting patients with autoimmune diseases for nonmyeloablative transplants from allogeneic stem cell donors. Research opportunities abound, but recruitment challenges restrict study entry due to organ impairment from advanced autoimmune disease or insurance denial of coverage for HCT. However, within several NIH sponsored trials there are ongoing immunologic, genomic and mechanistic studies to further understand the molecular mechanisms of autoimmunity, immune regulation and response to treatment. These clinical trials will provide basic scientists with insight into immunoregulatory pathways and clinicians with a context to weigh the progress and evidence in this evolving treatment for autoimmune diseases. Copyright 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.