Stem cell transplantation (SCT) for autoimmune disease is handicapped by a lack of definitive clinical trials able to demonstrate an overall benefit. This deficiency will become more problematic as the impetus grows to introduce and evaluate additional technologies intended to improve the safety and efficacy of the procedure. The development of effective surrogate analyses to predict outcome by measuring resurgent autoimmune clones or by genomic- and proteomic-based technologies to detect early disease recurrence may be of value in assessing the benefits of these modifications without the need for full-scale, long-term, randomized trials. The introduction of safer allogeneic transplantation techniques may increase the effectiveness of the procedure, while work on marrow stem cell plasticity and/or fusion suggests that SCT may serve not simply to halt the autoimmune process, but also to contribute cells capable of healing or regenerating diseased organs. Finally, the introduction of therapeutic transgenes into transplanted cells may further increase the effectiveness of SCT, although the regulatory complexities of gene therapy trials will probably delay this process. All these innovations will ensure that the next decade will see major changes in the practice and purpose of SCT for autoimmune disease.