The regenerative tissues such as hair follicles, intestine and teeth have a particular microenvironment known as “stem cell niche” which houses stem cells and act as a signaling center to control stem cell fate. The precise and timely regulation of stem cell renewal and differentiation is essential for tissue formation, growth and homeostasis over the course of a lifetime. However, the molecular underpinning to control this regulation is poorly understood. To address this issue, we use the continuously growing mouse incisor as a model to study the gene regulatory network which controls dental epithelial stem cell (DESC) maintenance, growth and craniofacial morphogenesis. We found FoxO6, a transcription factor mainly expressed in the brain and craniofacial region, control DESC proliferation by regulating Hippo signaling. FoxO6 loss-of-function mice undergo increases in cell proliferation which finally leads to lengthening of the incisors, expansion of the face and skull and enlargement of the mandible and maxilla. We have screened three human FOXO6 single nucleotide polymorphisms which are associated with facial morphology ranging from retrognathism to prognathism. Our study also reveals that Sox2 and Lef-1, two markers for early craniofacial development, are regulated by Pitx2 to control DESC maintenance, differentiation and craniofacial development. Conditional Sox2 deletion in the oral and dental epithelia results in severe craniofacial defects, including ankyloglossia, cleft palate, arrested incisor development and abnormal molar development. The loss of Sox2 in DESCs leads to impaired stem cell proliferation, migration and subsequent dissolution of the tooth germ. On the other hand, conditional overexpression of Lef-1 in oral and dental epithelial region increases DESC proliferation and creates a new labial cervical loop stem cell compartment in dental epithelial stem cell niche, which produces rapidly growing long “tusk-like” incisors. Interestingly, Lef-1 overexpression rescues the tooth arrest defects but not the ankyloglossia or cleft palate in Sox2 conditional deletion mice. Our data also reveal that miRNA and histone remodeler are involved in regulating DESC proliferation and craniofacial morphogenesis. We describe a miR-23a/b:Hmgn2:Pitx2 signaling pathway in regulating dental epithelial cell growth and differentiation. Pitx2 activates expression of amelogenin which is the major protein component for enamel deposition. This activation can be repressed by the chromatin-associated factor Hmgn2. miR-23a and miR-23b directly target Hmgn2, leading to the release of the Hmgn2 inhibition of Pitx2 transcriptional activity and thus enhance Amelogenin production. Phenotypically, ablation of Hmgn2 in mice results in an overgrowth of incisors with increased Amelogenin expression. The findings in this study increase our current understanding of the molecular regulation of dental epithelial stem cell fate. It not only highlights new gene regulatory network that controls dental stem cell maintenance, growth and craniofacial morphogenesis, but also sheds new light on developing novel stem cell therapy or gene therapy for tooth regeneration and dental diseases.