In 1867 the German pathologist Cohnheim hypothesized that non-hematopoietic, bone marrow-derived cells could migrate through the blood stream to distant sites of injury and participate in tissue regeneration. In 1868, the French physiologist Goujon studied the osteogenic potential of bone marrow on rabbits. Friedenstein demonstrated the existence of a nonhematopoietic stem cell within bone marrow more than a hundred years later. Since this discovery, the research on mesenchymal stem cell (MSC) has explored their therapeutic potential. The prevalent view during the second century was that mature cells were permanently locked into the differentiated state and could not return to a fully immature, pluripotent stem-cell state. Recently, Japanese scientist (first orthopaedist) Shinya Yamanaka proved that introduction of a small set of transcription factors into a differentiated cell was sufficient to revert the cell to a pluripotent state. Yamanaka shared the Nobel Prize in Physiology or Medicine and opened a new door for potential applications of MSCs. This manuscript describes the concept of MSCs from the period when it was relegated to the imagination to the beginning of the twenty-first century and their application in orthopaedic surgery.