Type 1 Diabetes (T1D) and Systemic Lupus Erythematosus (SLE) are two autoimmune diseases for which there is no definitive cure. Mesenchymal stem cells (MSC) transplantation is being tested as a therapeutic option in clinical trials for these two diseases. MSCs possess three important characteristics which could be exploited in cell-based approaches for autoimmune conditions: 1) they are potent immunomodulators, exerting suppressive functions on immune effector cells and orchestrating the action of other regulatory cells; 2) they can stimulate tissue repair and regeneration mechanisms; 3) they have shown a good safety profile in clinical trials, including a limited risk of tumour formation. Multiple clinical trials of MSC transplantation in patients with these diseases are ongoing. Here we review the results reported so far and highlight key emerging findings. These trials confirm the safety profile of this type of transplantation. In a cohort of T1D patients, the transplantation of autologous bone marrow-derived MSCs was associated with preservation of beta cell function over a 1-year follow-up. In a cohort of T1D patients who received autologous bone marrow-derived mononuclear cells along with umbilical cord-derived MSCs transplantation, beta cell function increased during the 1-year follow-up. In both studies, control patients experienced a decline in beta cell function. Non-randomized studies tested the transplantation of bone marrow- and umbilical cord-derived MSCs in patients affected by treatment-refractory SLE: the disease activity index improved, and immunologic parameters suggested partial remission from autoimmunity. The outcomes of these trials indicate that MSC transplantation is a safe procedure, and they suggest that MSCs may have efficacy in controlling the effects of the autoimmune processes. These findings should encourage larger and long-term randomized controlled studies of MSC transplantation in autoimmune disease to confirm safety and better assess efficacy.