Written for an audience of clinicians and young researchers who are exposed to MSCs in their work, this work summarizes recent findings pertaining to the definition and characterization of MSCs in skeletal tissues and discusses the mechanisms of their actions in regeneration of bone in vivo. The authors describe recent findings pertaining to the efficacy of MSC therapies in animal models and in human clinical trials and bring together literature showing that the ways MSCs are extracted, expanded and implanted can considerably affect bone formation outcomes. Finally, it presents the latest knowledge on the nature of native MSCs in skeletal tissues, which provide a platform for novel in situ tissue regeneration approaches for systemic bone disease such as osteoporosis.