Despite decades of research, remaining safety concerns regarding disease transmission, heterotopic tissue formation, and tumorigenicity have kept stem cell-based therapies largely outside the standard-of-care for musculoskeletal medicine. Recent insights into trophic and immune regulatory activities of mesenchymal stem cells (MSCs), although incomplete, have stimulated a plethora of new clinical trials for indications far beyond simply supplying progenitors to replenish or re-build lost/damaged tissues. Cell banks are being established and cell-based products are in active clinical trials. Moreover, significant advances have also been made in the field of pluripotent stem cells, in particular the recent development of induced pluripotent stem cells. Their indefinite proliferation potential promises to overcome the limited supply of tissue-specific cells and adult stem cells. However, substantial hurdles related to their safety must be overcome for these cells to be clinically applicable.