The earliest events in endochondral ossification, whether in the formation of the skeleton during embryogenesis or in the regeneration of a bone during fracture healing, involve the establishment of a tissue-specific plan of gene expression arising from pluripotent mesenchymal cells. Recent data from studies of vertebrate limb bud development implicate gradients of diffusable morphogens that specify complex patterns of position-specific gene expression. Diffusable signaling molecules involved at the earliest stages of tissue development include fibroblast growth factors, platelet derived growth factors, bone morphogenetic proteins, transforming growth factor beta, and sonic hedgehog; there are undoubtedly others. An equally elaborate array of trans-membrane receptors in the tyrosine kinase and serine-threonine kinase signaling pathways are responsible for transducing these morphogenetic signals and for establishing boundaries of gene expression. Nuclear signals for transcriptional activation, such as the fos-jun proto-oncogene family and homeobox genes, are also involved in the specification and modification of morphogenetic plans. While much has been learned recently about the presence and interaction of these growth factors and transcription factors in the development of the vertebrate limb bud, very little is known about their presence and interaction in the earliest stages of post-natal bone formation at a fracture site or in heterotopic osteogenesis. Fibrodysplasia ossificans progressiva (FOP) a rare genetic disorder of heterotopic ossification, provides a unique opportunity to study the role of these morphogens and proto-oncogenes in the earliest events of endochondral bone formation.