It has long been known from the pioneering work of Friedenstein and Owen that bone marrow contains a non-hematopoietic multipotent stem/progenitor cell that has the ability to recreate cartilage, or a bone/marrow organ, now known as a skeletal stem cell (SSCs). As does bone, SSCs are formed by neural crest and multiple specifications of mesoderm during embryonic development. Their biological activities are best probed by a series of rigorous in vitro and in vivo assays, which have established the skeletal stem cell as not only critical for bone homeostasis, but also for normal hematopoiesis based on their contribution to the hematopoietic stem cell niche. These cells have become an important tool not only for bone regeneration, but also for modeling of skeletal and certain hematopoietic disorders.