In this chapter we examine whether criteria usually defining adult tissue stem cells apply to mesenchymal stem cells (MSCs) that give rise to cells of the skeletal connective tissues. MSCs appear to constitute a heterogeneous population of undifferentiated and committed, lineage-primed cells, capable of: homing upon engraftment to a number of growth microenvironments, extensive proliferation, producing large numbers of differentiated progeny, and functional tissue repair after injury. In addition, MSCs are extensively distributed throughout tissues, and bone marrow MSCs provide the stromal component of the niche of hematopoietic stem cells. The capacity of apparently differentiated mesenchymal cells to shift their differentiation pathway with changing microenvironmental conditions (known as differentiation plasticity) may be due to de-differentiation and reprogramming in MSCs. Because they present several features setting them apart from other stem cells, MSCs may constitute another paradigm for stem cell systems, where self-renewal and hierarchy are no longer essential, but where plasticity is the major characteristic.