The identification of Runx2 (runt-related protein 2) function has greatly advanced the understanding of skeletal development over the last 5 years. Runx2 is regulated transcriptionally and post-translationally through the activity of many identified factors, although, the physiological significance of each remains to be demonstrated. The interaction of Runx2 with other transcription factors and cofactors has been shown to be important in Runx2-dependent gene regulation. Runx2 plays important roles in multiple steps of skeletal development. Runx2 determines the lineage of osteoblasts from multipotent mesenchymal cells, enhances osteoblast differentiation at an early stage, and inhibits osteoblast differentiation at a late stage. Runx2 plays crucial roles in chondrocyte maturation and in the specification of cartilage phenotypes. Furthermore, Runx2 is involved in vascular invasion into cartilage and osteoclastogenesis. Therefore, the determination of Runx2 function and the investigation of the cascades of Runx2-dependent gene regulation are important in the elucidation of skeletal biology. J. Cell. Biochem. 87: 1–8, 2002. © 2002 Wiley-Liss, Inc.