High-dose immunosuppression followed by autologous hematopoietic stem cell therapy (HSCT) has the promise of long-term response after a short, intense period of immunosuppressive therapy but it is associated with an increased risk of serious short-term complications. HSCT induces major clinical responses in about 65% of patients with SLE who failed standard therapies. In some of these patients such responses are durable for at least several years, but the curative potential of this procedure in severe SLE is still unknown. Procedure-related mortality varies among studies between 5 and 12% and seems to be lower in relatively larger single center studies. Until more reliable estimates of the actual risks and long-term outcomes become available, patients with potentially life-threatening or disabling major organ involvement who are in acceptable general medical condition should be considered for autologous HSCT if they have failed a reasonable course of standard immunosuppressive therapy. To accomplish the best therapeutic and scientific results, it is necessary to treat all patients in carefully planned protocols by specialized teams of lupus specialists and transplanters. All immunoablative protocols should incorporate carefully planned studies of immune reconstitution to understand the mechanisms of cure or failure.