The Cbfa1/Runx2 is an important transcription factor necessary for osteoblast differentiation and bone formation. However, the signaling pathways regulating Runx2 activity are just beginning to be understood. Inconsistencies between Runx2 mRNA or protein levels and its transcriptional activity suggests that posttranslational modification and/or protein‐protein interactions may regulate this factor. Runx2 can be phosphorylated and activated by the mitogen‐activated protein kinase (MAPK) pathway. This pathway can be stimulated by a variety of signals including those initiated by extracellular matrix (ECM), osteogenic growth factors like bone morphogenic proteins (BMPs) and fibroblast growth factor‐2 (FGF‐2), mechanical loading and hormones such as parathyroid hormone (PTH). Protein kinase A (PKA) may also phosphorylate/activate Runx2 under certain conditions. In addition, Runx2 activity is enhanced by protein‐protein interactions as are seen with PTH‐induced Runx2/AP‐1 and BMP‐mediated Runx2/Smads interactions. Mechanisms for interaction with Runx2 are complex including binding of distinct components such as AP‐1 factors and Smads proteins to separate DNA regions in target gene promoters and direct physical interactions between Runx2 and AP‐1/Smad factors. Post‐translational modifications such as phosphorylation may influence interactions between Runx2 and other nuclear factors. These findings suggest that Runx2 plays a central role in coordinating multiple signals involved in osteoblast differentiation. © 2002 Wiley‐Liss, Inc.