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Current systemic therapies are rarely curative for patients with severe life-threatening forms of autoimmune diseases (ADs). During the past 15 years, autologous hematopoietic stem cell transplantation has been demonstrated to cure some patients with severe AD refractory to all other available therapies. As a consequence, ADs such as lupus and scleroderma have become an emerging indication for cell therapy. Multipotent mesenchymal stem cells (MSCs), isolated from bone marrow and other sites, display specific immunomodulation and anti-inflammatory properties and appear as ideal tools to treat such diseases. The present update aims at summarizing recent knowledge acquired in the field of MSC-based therapies for lupus and scleroderma.