Craniofacial defects due to specific genes in mice are the major subject of our investigations. Mutations that change the biochemistry of chondrocytes resulting in craniofacial skeletal disturbances and mutations that change the ability of epithelial cells to keratinize can result in malformations such as cleft lip and cleft palate, exancephaly and malocclusion. Other genes modify the ability of embryos to tolerate drug treatment, diets or environmental agents that cause similar malformations. These mouse genetic test systems are produced using uniform, highly inbred, strains and timed mating resulting in well defined stages of development with tissues at critical periods of susceptibility for in vivo or in vitro study. Cells from embryo tissues of appropriate genetic type and developmental stage are treated in culture using isotopically labeled precursors for specific structural molecules in order to determine the mechanisms of gene action in development and the mechanisms of teratogenesis. A high degree of genetic definition, available among mammals only in mice, is essential to assure molecular specificity of biochemical defects of development.