AbstractFollowing the identification of bone marrow multipotent cells that could adhere to plastic and differentiate along numerous mesenchymal lineages in vitro, a considerable effort has been invested in characterizing and expanding these cells, which are now called “mesenchymal stem cells” (MSCs), in vitro. Over the years, numerous lines of evidence have been provided in support of their plasticity, their extraordinary immunomodulatory properties, their potential use for tissue engineering purposes, as well as their ability to be recruited to sites of injury, where they might contribute a “natural in vivo system for tissue repair.” Moreover, some studies have attempted the characterization of their cell‐surface specific antigens and of their anatomical location in vivo. Lastly, it has been shown that similar cells could be also isolated from organs other than the bone marrow. Despite this impressive body of investigations, numerous questions related to the developmental origin of these cells, their proposed pluripotency, and their role in bone modeling and remodeling and tissue repair in vivo are still largely unanswered. In addition, both a systematic phenotypic in vivo characterization of the MSC population and the development of a reproducible and faithful in vivo assay that would test the ability of MSCs to self‐renew, proliferate, and differentiate in vivo are just beginning. This brief review summarizes the current knowledge in the field of study of MSCs and the outstanding questions. J. Cell. Biochem. 109: 277–282, 2010. © 2009 Wiley‐Liss, Inc.