Hedgehog ligands bind to protein patched homologue 1 (PTC), a conserved receptor that activates the GLI family of transcription factors, which are involved in development, disease and skeletal repair processes. During embryonic development, hedgehog signalling helps to pattern the limbs and plays a critical part in regulating chondrocyte differentiation and osteogenesis during the longitudinal growth of long bones. This signalling pathway also regulates mesenchymal cell differentiation during skeletal repair and regeneration. In pathologic and degenerative processes, such as osteoarthritis or cartilaginous tumour formation, hedgehog signalling is dysregulated. Several pharmacologic strategies can modulate hedgehog signalling, and targeting this pathway could lead to the development of novel therapeutic approaches. For example, by precisely regulating the level of activity of the hedgehog signalling pathway, the pace of degeneration in osteoarthritis could be slowed, bone repair could be enhanced, and cartilaginous tumour cell viability could be inhibited. As such, regulation of hedgehog signalling could be manipulated to safeguard skeletal health.