OBJECTIVE Cell therapy with mesenchymal stromal cells (MSC) has emerged as a promising tolerance-inducing strategy, as MSC are potent modifiers of immune cells within adaptive as well as innate arm of the immune system. Here, we review recent evidence on both the beneficial and deleterious effect of MSC in experimental models of solid organ transplantation as well as first clinical experiences of MSC therapy in kidney transplant recipients. RESULTS MSC are able to reprogram macrophages toward an anti-inflammatory phenotype capable to regulate antigraft immune response. This interaction is mediated mainly by TNF-α-induced-protein-6. Conversely, MSC also take on a proinflammatory phenotype and actually could worsen graft outcome. MSC in clinical transplantation is in its infancy and nobody so far has attempted to or provided evidence that this cell-based therapy is capable to promote operational tolerance. There are, however, supporting data of the ex-vivo immunoregulatory activity of MSC in treated patients. CONCLUSIONS MSC have a great potential as a tolerance-promoting cell therapy. Extensive investigations are still needed to dissect the mechanism(s) of action of MSC, particularly in the setting of a proinflammatory environment, and to establish specific assays for monitoring MSC-treated patients to define the protolerogenic potential of MSC-based therapy in kidney transplantation.