An essential aspect of craniofacial development is chondrogenesis, the process of chondrocyte differentiation from multipotent neural crest cells. These multipotent cells delaminate from the neural tube during neurulation, travel along specific routes and differentiate into various cell types forming different tissues. The formation of this wide range of neural crest cell derivatives is dependent on multiple factors, including transcription factors, extracellular matrix proteins, and growth factors. Sox proteins are transcription factors that play a role during development of various tissues. L-Sox5, Sox6 and Sox9 play a role in the differentiation of neural crest cells into chondrocytes by binding to regulatory elements, enhancing the expression of chondrocyte-specific collagens. Minor fibrillar collagens V and XI contribute to chondrogenesis of the craniofacial skeleton by mechanisms that include the regulation of collagen fibrillogenesis and a bridging function between major fibrillar collagens and other cell or matrix molecules. However, the mechanism of regulation is not fully understood. Disruption of craniofacial development during chondrogenesis can lead to Stickler Syndrome or Campomelic Dysplasia as a result of collagen XI and Sox9 mutations, respectively. Here, we focus on potential additional mechanisms by which the extracellular matrix plays a role in Sox-mediated chondrogenesis during craniofacial development. PTHrP may be the link between the expression of extracellular matrix and Sox transcription factor family-mediated regulation of chondrogenesis, creating a regulatory cycle that supports growth and development of cartilage-derived structures.