Regenerative medicine is a fascinating field which aims to harness the potential of biological therapeutics to achieve true regeneration of tissues and organs. While full of promises, there are still many challenges to address in this young discipline, mainly because biological therapeutics are complex in their composition and mode of action. We focus on multipotent mesenchymal stromal cells (MSC) and their context-dependent fate, working towards strategies that fully exploit their therapeutic potential. It is intriguing to witness the growing understanding of their functions in health and disease, and to contribute our pieces to the big puzzle.