The last decade was dominated by dissemination of the notion that postnatal “mesenchymal stem cells,” found primarily in bone marrow but also in other tissues, can generate multiple skeletal and nonskeletal tissues, and thus can be exploited to regenerate a broad range of tissues and organs. The concept of “mesenchymal stem cells” and its applicative implications represent a significant departure from the solidly proven notion that skeletal stem cells are found in the bone marrow (and not in other tissues). Recent data that sharpen our understanding of the identity, nature, origin, and in vivo function of the archetypal “mesenchymal stem cells” (bone marrow skeletal stem cells) point to their microvascular location, mural cell identity, and function as organizers and regulators of the hematopoietic microenvironment/niche. These advances bring back the original concept from which the notion of “mesenchymal stem cells” evolved, and clarify a great deal of experimental data that accumulated in the past decade. As a novel paradigm emerges that accounts for many facets of the biology of skeletal stem cells, a novel paradigm independently emerges for their applicative/translational use. The two paradigms meet each other back in the future. J. Cell. Biochem. 112: 1713–1721, 2011. © 2011 Wiley-Liss, Inc.