To elucidate the basal metabolism of Mesenchymal Stromal Cells (MSCs), as well as knowing how they are activated, can bring important clues to a successful cell-based therapy. Naive MSCs, in their niche, mainly keep the local homeostasis and the pool of tissue stem cells. Once activated, by an injury, MSCs’ response leads to a lot of physiological differences in its metabolism that are responsible for its healing process. Since endogenous MSC seems to be ineffective in pathologic and aging conditions, cell-based therapy using MSC is focused on administration of exogenous MSC in patients to exert its healing functions. From quiescent to activated state, this “Metabolic Shifting” of MSC interferes directly in its secretion and cellular-derived particle generation. We will address here the differences between the MSCs activation phases and how they can modify the MSCs metabolism and its function. Moreover, understanding MSC in their niche and its damped function in pathologic and aging processes can improve stem cell-based therapies.