Experimental investigations and serendipitous clinical reports had indicated that hematopoietic stem cell transplantation (HSCT) could represent a new powerful procedure for treating severe autoimmune diseases (SADs). Although the therapeutic potential of allogeneic transplantation appeared theoretically potentially curative, the almost paradoxical results by van Bekkum and his group indicated that the autologous procedure also had outstanding therapeutic potential. The European and American experience includes by now an estimated number of autologous transplants for SADs of well over 1000 cases. The December 2008 issue of Autoimmunity contains the most recent information about the various autoimmune diseases treated with autologous and allogeneic HSCT. This perspective, rather than reporting on already published clinical trials, focuses on the main questions connected with autologous ASCT – that is, its safety, its currently explored advantages and disadvantages versus the best available nontransplant procedures and its mechanism of action. Allogeneic transplants for non-coincidental diseases are still too few to attempt to draw conclusions, but its scientific and ethical utilization relies uniquely in the pursuit of cure.