Systemic sclerosis (SSc) with diffuse cutaneous scleroderma and visceral organ involvement is associated with considerable morbidity and mortality almost from its inception. Since the risk of accrual and progression of skin and organ complications is greatest in the first few years of SSc, the best opportunity for significantly modifying the course of SSc (prolonging survival and/or preventing or lessening the progressivity of organ involvement) is probably limited to the first 3 to 4 years. Transplantation of autologous stem cells (ASCT), after immune ablation of the host, has the potential to modify the disease course. Even though the mortality risk of ASCT is low (< 2% mortality in the first year), the mortality risk of the disease being treated must justify that risk. We suggest that patients with diffuse Sc of short duration (< 3 years from the first non-Raynaud sign/symptom) with evidence of at least mild involvement of heart, lung, or kidney, have sufficiently severe disease to warrant ASCT. In contrast, we suggest that patients with severe/end stage organ involvement have progressed to the point where ASCT will not be helpful in improving that degree of organ involvement.