During the last decade, mesenchymal stromal cells (MSCs) have generated numbers of clinical trials to address inflammatory diseases such as GVHD, Crohn’s disease and lupus. Animal models and therapeutic protocols in patients have demonstrated their anti-inflammatory and immunosuppressive properties towards adaptive immune cells. However, the basis of their immune suppression remains hotly debated. In the present review, we discuss the comparative isolation of human and rodent MSCs, their respective immune properties, whether constitutive or licensed by inflammatory or immune reactions, as well as differential efficacy as observed in GVHD clinical trials and related mouse models. Rodent MSCs display a number of immune differences with human MSCs regarding to ease of isolation, licensing pathways resulting in immunosuppression, and expression of immune mediators. These observations urge for caution when translating results generated in murine models into clinical settings.