Clefts of the palate are common birth defects requiring extensive treatment. They appear to be caused by multiple genetic and environmental factors during palatogenesis. This may result in local changes in growth factors, extracellular matrix (ECM), and cell adhesion molecules. Several clefting factors have been implicated by studies in mouse models, while some of these have also been confirmed by genetic screening in humans. Here, we discuss several knockout mouse models to examine the role of specific genes in cleft formation. The cleft is ultimately caused by interference with shelf elevation, attachment, or fusion. Shelf elevation is brought about by mesenchymal proliferation and changes in the ECM induced by growth factors such as TGF-betas. Crucial ECM molecules are collagens, proteoglycans, and glycosaminoglycans. Shelf attachment depends on specific differentiation of the epithelium involving TGF-beta3, sonic hedgehog, and WNT signaling, and correct expression of epithelial adhesion molecules such as E-cadherin. The final fusion requires epithelial apoptosis and epithelium-to-mesenchyme transformation regulated by TGF-beta and WNT proteins. Other factors may interact with these signaling pathways and contribute to clefting. Normalization of the biological mechanisms regulating palatogenesis in susceptible fetuses is expected to contribute to cleft prevention.