Transforming growth factor-beta (TGF-β) regulates a large variety of cellular activities. Binding of TGF-β to its cell surface receptor triggers several signaling cascades, among which the TGF-β-Smad pathway is the most extensively studied. TGF-β also activates protein kinases, including MAPK, PKA and PKC, and modulates gene expression via its delicate interaction with other signaling pathways. During endochondral bone formation, TGF-β acts as a potent inhibitor of the terminal differentiation of epiphyseal growth plate chondrocytes. This effect appears to be primarily mediated by Smad molecules, although MAPK-ATF2 signaling is also involved. The rate of chondrocyte maturation is tightly regulated through the interactions of Smad-mediated signaling, the Wnt signaling pathway, and the transcription factor Runx2. Improving our understanding of the exact mechanisms underlying TGF-β-mediated signaling pathways and their effects may greatly impact the diagnosis and treatment of many common orthopaedic diseases.