Better understanding of the pathogenesis of tissue fibrosis, and especially the pivotal role of the extracellular matrix components, shed new light on the use of several immunosuppressive drugs to treat systemic sclerosis. We review the recent experimental data demonstrating the specific antifibrotic effect of several immunosuppressive drugs, independent of their immunosuppressive action, in light of the clinical results obtained when treating severe systemic sclerosis patients. Refined analysis of the molecular mechanisms underlying the direct antifibrotic effects of these immunosuppressive drugs (rapamycin and mycophenolate mofetil) will contribute to improve the therapeutic strategy in systemic sclerosis patients.