Pamela G. Robey, Editor appear and begin to function. The primitive bony collar established by these osteoblasts becomes eroded by osteoclasts to allow vascular invasion and the formation of a marrow cavity. Vascular invasion brings osteogenic cells, which had previously differentiated in the periosteum, into the marrow cavity as perivascular cells. The development of sinusoids (characterized by slow blood flow and cell-permeable endothelial walls) then allows for seeding of the extravascular environment with bloodborne hematopoietic stem cells (HSCs), which then interact with the primitive stromal microenvironment. This interaction permits hematopoiesis to be established; it may also simultaneously arrest further osteogenic differentiation by primitive stromal cells, thus allowing a marrow space to develop within what would otherwise be solid bone. A continuous network of cells is ultimately formed within the marrow space. It extends from the abluminal aspects of blood vessels to bone surfaces through the stromal cells interspersed among hematopoietic cells. This explains the physical and biological continuity of bone and marrow, which together form a single organ—the bone–bone marrow organ. Stromal cells in the primitive nonhematopoietic marrow, which appear much like preosteoblasts, divide actively, whereas stromal cells of hematopoietically active marrow are mitotically quiescent but continue to express the osteoblastic marker alkaline phosphatase at high levels (9). Formation of the marrow cavity and marrow stroma requires the pivotal transcription factor, cbfa1, which controls osteogenic differentiation and drives bone formation (10, 11). In development, the physical emergence of marrow stromal cells lies downstream of the physical emergence of bone and bone-forming cells, and, of course, downstream of the relevant transcriptional control (Figure 1). In postnatal organisms, cbfa1 is commonly, and perhaps consistently, expressed in clones and nontransformed lines of human or murine marrow stromal cells but does not predict their actual osteogenic capacity upon in vivo transplantation (12). Expression of cbfa1 in these same cell strains does not prevent differentiation towards nonosteoblastic phenotypes, such as adipocytes or chondrocytes. Considered along with the temporal and developmental priority of osteogenic differentiation over the physical emergence of marrow stromal cells, these observations suggest that osteogenic commitment directed by cbfa1 occurs upstream of the ontogeny of marrow stromal cells, which are the postnatal precursors of osteogenic cells. These cells retain expression of cbfa1, possibly as a legacy of their osteogenic origins, but they remain capable of entering multiple differentiation pathways and are not committed to an obligate osteogenic fate. If cbfa1 is viewed as a master gene for osteogenic commitment, then marrow stromal cells are reversibly committed and multipotential cells.