Extracellular matrix metabolism plays a central role in development of skeletal tissues and in most orthopaedic diseases and trauma such as fracture or osteotomy repair, arthritis, cartilage repair, and congenital skeletal deformity. During development or disease, specific genes must be expressed in order to make or repair appropriate extracellular matrix. For example, specific gene expression patterns are characteristic of bone and cartilage. The precise expression pattern depends on a balance of positive and negative transcription factors, proteins that control the synthesis of mRNA from the specific gene. In cartilage, a number of studies indicate that Sox transcription factors are critical positive regulators in genes such as COL2A1, COL9A2, COL11A2, aggrecan, and CD-RAP. In addition, negative regulators are also essential to fine tune gene regulation in chondrocytes and to turn off gene expression in noncartilaginous tissues. Negative transcription factors in cartilage include partial differentialEF-1, snail/slug, CYRBP1, NT2, and C/EBP. Runx2 and osterix are critical transcription factors for osteogenesis but also have some influence on chondrogenesis. The availability of cis-regulatory sites in specific genes combined with the availability of transcription factors in the nucleus determines the level of gene expression.