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Improvement of long-term outcome of kidney transplantation has reached its limits due to consequences of efficient, but nonspecific immunosuppressive drugs. Mesenchymal stromal cells (MSC) have been proposed as an alternative strategy for more refined therapy. The interest in MSCs comes from their anti-inflammatory properties on the one hand and their propensity to ameliorate tissue damage and mediate repair on the other hand. First clinical trials have demonstrated that administration of MSCs in kidney transplant recipients is safe and feasible, and follow-up studies have been initiated with the desired clinical efficacy to reduce ischemia-reperfusion injury, to prevent/reverse acute transplant rejection, and to improve long-term transplant survival with minimization of immunosuppression. To further promote wider application of MSC in renal transplantation, it is of importance to determine efficacy, to increase the understanding of the mechanism of action, and to develop tools to identify eligible patients. In addition, we should overcome challenges particularly at the transition of early phase I studies to more advanced stages of clinical development. In this review, latest insights, first clinical experiences, and future challenges of MSC in solid organ transplantation are discussed.