Abstract Mesenchymal stem cells (MSCs) were initially defined by their capacity to differentiate into connective tissue cell lineages and support hematopoiesis. More recently, MSCs have demonstrated some degree of therapeutic efficacy in a broad range of diseases including neurological and auto-immune disorders, stroke, diabetes, and chronic inflammatory conditions. An emerging paradigm suggests that MSCs alter the tissue microenvironment via paracrine signaling to induce angiogenesis, alter immune cell function, block inflammation, and stimulate growth of host cells to affect tissue repair. However, these activities appear at odds with the term mesenchymal stem cell, which by definition implies a rare cell population that through a process of self-renewal yields progenitors that differentiate hierarchically into connective tissue cell types to maintain tissue homeostasis.