Effective treatments for severe systemic sclerosis (SSc) have not been identified. SSc is associated with high levels of morbidity and mortality related to functional impairment and organ dysfunction. The pathogenesis of SSc, as with all autoimmune disorders, is thought to involve the interplay between genetic background and environmental exposures. Abundant evidence exists for activation of humoral and cellular immunity in SSc. These immune and inflammatory mechanisms almost certainly play a role in vascular damage and activation of pathways that lead to fibrosis. However, the types and intensities of immunomodulatory therapies employed in other connective tissue diseases have not proved as useful in patients with SSc. The question remains if increasing the intensity of immunosuppression will prove a more successful strategy. Preliminary studies of intensification of therapy to immunoablative and myeloablative levels with hematopoietic stem cell rescue have been performed and appear promising. New studies to compare these approaches with conventional immunomodulatory therapy are underway.