Many in vitro and in vivo data are available supporting the role of mesenchymal stromal cell (MSC) licensing in the induction of a measurable and effective immune regulation. The failure of some MSC-based protocols for immune modulation in animal models and in human clinical trials may be explained by either lack of a proper licensing by inflammatory microenvironment or wrong timing in MSC administration. Thus, optimization of MSC use for immune-regulating purposes is required to maximize their beneficial effects.