Recent reports have highlighted that adult stem cells are granted with yet poorly understood properties other than multipotentiality. In particular, mesenchymal stem cells (MSCs) represent a subset of adult stromal cells that can down-regulate several functions of the immune cells. In addition, MSCs may promote survival of damaged cells and tissues through paracrine mechanisms, possibly under the guidance of environmental cues. Thus, MSCs clinical application in autoimmune diseases seems an appealing opportunity and preclinical results in different experimental models of autoimmunity further support this strategy. Despite the absolute need for caution related to several clinical and technical issues, MSCs are now on the edge of a new era of clinical applications.