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An experimental approach and logic are presented for the regeneration of skeletal tissues that focus on the recapitulation of embryonic events starting with an uncommitted progenitor cell population that the authors refer to as mesenchymal stem cells. The repair and regeneration of articular cartilage, which itself has no repair potential, is the subject of this presentation. Full thickness cartilage defects were created in the medial condyle of the distal femur. Self repair (empty defects), articular chondrocytes (allografts), and autologous mesenchymal stem cells were used and the results are reported in selected examples from more than 800 rabbit knees. The optimal number of the appropriate cells delivered in a supportive vehicle to a defect pretreated with a dilute trypsin solution to optimize the integration of repair with normal host cartilage provides a methodology in which regeneration of articular cartilage can be observed. The principles have relevance to the clinical repair and regeneration of cartilage and other skeletal defects.