Skeletal defects arising from developmental abnormalities trauma, infection or neoplasia as well as degenerative diseases such as osteoarthritis and osteoporosis, severely diminish the quality of life. These disorders are in principle, treatable by stem cell-based approaches. Embryonic stem (ES) cells are pluripotential cell lines established from pre-implantation embryos. Human ES (hES) cells can be differentiated in vitro into many cell types of therapeutic relevance although most protocols lead to complex, mixed cell populations. We have recently reported the directed differentiation of hES cells under conditions in which the majority of cells expressed osteogenic markers and were associated with calcification in vitro. Adult stem cells, in particular mesenchymal stem cells (MSCs), have more restricted potentiality than ES cells. While MSCs show promise in tissue engineering and transplantation studies for repair of bone and cartilage they also result in mixed populations of differentiated cells. The complexity/multipotentiality of the engrafted populations frequently gives rise to unwanted cell types such as adipocytes, a potential problem that is particularly pertinent in aged recipients. It remains to be seen if this problem also arises with ES-derived cells.  In order to enable the efficient repair of bone under the sub-optimal conditions found in the aged or diseased patient, populations of cells already committed to the osteogenic lineage are preferred. While a subset of MSCs can be readily differentiated to mineralizing osteoblasts in vitro it has been impossible to study the processes involved in the establishment of that population from marrow-derived cells because of their limited number and short proliferative lifespan. With the development of hES-derived osteogenesis we now have the opportunity to study the elusive osteoprogenitor in a system amenable to ll engineering and free of experimental variation due to the effect of multiple donors. Our broad long term objective is to provide combinations of osteoprogenitor cells, scaffolds and coatings sufficient to repair large scale bone defects in an animal model and to determine if viable grafts can be obtained from both hES and hMSC-derived material.