Autoimmune diseases afflict approximately 2% of the US population and span virtually every medical specialty. Most patients with autoimmune diseases have a normal life expectancy and are managed conservatively; however, a subset of patients have a progressive disease course associated with significant morbidity and mortality. High-dose cytotoxic therapy followed by autologous stem cell transplantation has been proposed as a novel treatment for severe autoimmune diseases. This review will focus on recent advances in the immunopathogenesis of autoimmunity and will review preliminary results of clinical trials employing hematopoietic stem cell transplantation for the treatment of autoimmunity.