While multipotent mesenchymal stromal cells (MSC) have been introduced into pre-clinical and clinical studies since the far sixties, their full potentials to regenerate tissues have been partially clarified. We retain several aspects shall be considered and improved to generate optimized regenerative potentials by MSC in humans. In this paper, starting from in vivo detection of MSC, we will describe technologies and models that in our hands allow: (1) to ex-vivo isolate and characterize MSC for clinical applications, (2) to assess their in vitro potency to regenerate tissues, (3) to create pre-clinical in vivo rational for their clinical implementation and, (4) to establish protocols for their delivery. The attempt to standardize these aspects for a specific clinical indication is an essential prerequisite to better define and challenge MSC biological properties. This applies particularly in case of multi-centric tissue regeneration studies, as is currently taking place in the REBORNE consortium sponsored by the FP7.