Allogeneic hematopoietic stem cell transplantation, after sublethal irradiation of recipient animals, is capable of inducing donor-specific tolerance facilitating subsequent organ transplantation. This approach could reintroduce tolerance in autoimmune diseases and it has been applied to treat autoimmune diseases with, however, a great susceptibility of recurrence. Mesenchymal stem cells (MSCs) present within the bone marrow could be critical to the immunosuppressive effect of the treatment. This tolerance induction may be useful in allogeneic transplantations, where low incidence of graft-versus-host disease was observed when the hematopoietic graft was coinjected with MSCs. In this paper, we discuss the use of MSCs in different therapeutic strategies either as immunosuppressive agents or genetically engineered to express molecules acting against the autoimmune process.