Skeletogenesis is a complex multi-step process, which involves many genes and pathways. The tightly regulated interplay between these genes in these pathways ensures a correct and timely organogenesis and it is imperative that we have a fair understanding of the major genes and gene families involved in the process. This review aims to give a deeper insight into the roles of 3 major transcription factor families involved in skeleton formation: Sox, Runx and Pax and to look at the human skeleotogenic phenotypes associated with mutations in these genes.