Hematopoietic stem cells (HSCs) are the earliest cells of the immune system, giving rise to B and T lymphocytes, monocytes, tissue macrophages, and dendritic cells. In animal models, adoptive transfer of HSCs, depending on circumstances, may cause, prevent, or cure autoimmune diseases. Clinical trials have reported early remission of otherwise refractory autoimmune disorders after either autologous or allogeneic hematopoietic stem cell transplantation (HSCT). By percentage of transplantations performed, autoimmune diseases are the most rapidly expanding indication for stem cell transplantation. Although numerous editorials or commentaries have been previously published, no prior review has focused on the immunology of transplantation tolerance or development of phase 3 autoimmune HSCT trials. Results from current trials suggest that mobilization of HSCs, conditioning regimen, eligibility and exclusion criteria, toxicity, outcome, source of stem cells, and posttransplantation follow-up need to be disease specific. HSCT-induced remission of an autoimmune disease allows for a prospective analysis of events involved in immune tolerance not available in cross-sectional studies.