The Runx (runt-related protein) family of transcription factors plays important roles in different tissues and cell lineages. Runx1 determines commitment to the hematopoietic cell lineage and Runx2 determines commitment to the osteoblastic lineage. Cbfβ is required for Runx1- and Runx2-dependent transcriptional regulation. Runx2 interacts with many other transcription factors and co-regulators in the transcriptional regulation of its target genes. Runx2 is essential for the commitment of multipotent mesenchymal cells into the osteoblastic lineage and inhibits adipocyte differentiation. Runx2 induces the gene expression of bone matrix proteins, while keeping the osteoblastic cells in an immature stage. Runx2 and Runx3 have redundant functions in chondrocytes, and they are essential for chondrocyte maturation. Runx2 directly induces Indian hedgehog (Ihh) expression and co-ordinates the proliferation and differentiation of chondrocytes. Therefore, elucidation of the signaling pathways through Runx2 and Runx3 will unravel the complex mechanism of skeletal development. © 2005 Wiley-Liss, Inc.