The current understanding of the origin and evolution of the genetic cassette for the vertebrate skeletal system is reviewed. Molecular phylogenetic analyses of fibrillar collagen genes, which encode the main component of both cartilage and mineralized bone, suggest that genome duplications in vertebrate ancestors were essential for producing distinct collagen fibers for cartilage and mineralized bone. Several data Indicate co-expression of the ancestral copy of fibrillar collagen with the SoxE and Runx transcription factors. Therefore, the genetic cassette may have already existed in protochordate ancestors, and may operate in the development of the pharyngeal gill skeleton. Accompanied by genome duplications in vertebrate ancestors, this genetic cassette may have also been duplicated and co-opted for cartilage and bone. Subsequently, the genetic cassette for cartilage recruited novel genetic material via domain shuffling. Aggrecan, acquired by means of domain shuffling, performs an essential role in cartilage as a shock absorber. In contrast, the cassette for bone recruited new genetic material produced by tandem duplication of the SPARC/osteonectin genes. Some of the duplicated copies of SPARC/osteonectin became secretory Cabinding phosphoproteins (SCPPs) performing a central role in mineralization by regulating the calcium phosphate concentration. Comparative genome analysis revealed similar molecular evolutionary histories for the genetic cassettes for cartilage and bone, namely duplication of the ancestral genetic cassette and recruitment of novel genetic material.