Scleroderma is a multisystem autoimmune disease characterized by an abnormal immune activation associated with the development of underlying vascular and fibrotic disease manifestations. This article highlights the current use of drugs targeting the immune system in scleroderma. Nonselective immunosuppression, and in particular cyclophosphamide, remains the main treatment for progressing skin involvement and active interstitial lung disease. Mycophenolate mofetil is a promising alternative to cyclophosphamide. The use of cyclosporine has been limited by modest efficacy and serious renal toxicity. Newer T-cell (sirolimus and alefacept) and B-cell (rituximab)-targeted therapies have provided some encouraging results in small pilot studies. Hematopoietic stem cell transplantation can be effective for severe fibrotic skin disease, but toxicity remains a concern. Clinical efficacy and safety of antifibrotic treatments (e.g., imatinib) await confirmation. Newer biological agents targeting key molecular or cellular effectors in scleroderma pathogenesis are now available for clinical testing.