This review focuses on the regulation of skeletal development and maintenance by Runx2 and Sp7, including chondrocyte differentiation, osteoblast differentiation, osteoblast proliferation, mature osteoblast functions, diseases caused by RUNX2 and SP7, and the critical roles of Runx family transcription factors in osteoarthritis (OA). The gene discussed is SP7; the disease is osteoarthritis.