Immunosuppressive drugs constitute a heterogeneous group of therapeutic compounds, each with a unique mode of action and toxicity profile (Table 41.1). Their main function is to dampen the immune system – notably T and B lymphocytes – functionally and/or numerically, hence their utility in inducing remission and control of specific rheumatic manifestations that result from inflammation. Immunosuppressive drugs alone do not permanently correct the fundamental imbalance of immune regulation in autoimmune disease and, as such, they have only limited curative potential when used in standard doses. By contrast, immunoablative therapy and autologous hematopoietic stem cell transplantation (HSCT) corrects the fundamental imbalance in immune regulation in autoimmune disease and appears to result in significant mortality and morbidity benefit, albeit with a substantial potential risk. Biologic therapies directed at various cytokine and cellular targets hold the promise of more directed intervention, although the evidence for their efficacy in systemic sclerosis (SSc) remains limited.