Craniofacial tissues comprise highly evolved organs characterized by a relative lack of expression in the HOX family transcription factors. In the present study, we sought to define the epigenetic events that limit gene expression from undifferentiated neural crest cells to semi-differentiated odontogenic progenitors and to explore the effects of elevated levels of . The ChIP-chip data demonstrated high levels of repressive H3K27me3 marks on the gene promoters in ES and cranial neural crest cells when compared to the H3K4me3 marks, while the K4/K27 ratio was less repressive in the odontogenic progenitors, dental follicle, dental pulp, periodontal ligament fibroblasts, alveolar bone osteoblasts, and cementoblasts. The gene expression of multiple genes, especially those from the and clusters, was significantly elevated and many times higher in alveolar bone cells than in the dental follicle cells. In addition, the levels in the skeletal osteoblasts were many times higher in the trunk osteoblasts compared to the alveolar bone osteoblasts, and the repressive mark H3K27me3 promoter occupancy was substantially and significantly elevated in the alveolar bone osteoblasts when compared to the trunk osteoblasts. To explore the effect of elevated levels in craniofacial neural crest cells, expression was induced by transfecting cells with the Cdx4 transcription factor, resulting in a significant decrease in the mineralization markers, RUNX2, OSX, and OCN upon elevation. Promoting gene expression in developing teeth using the small molecule EZH2 inhibitor GSK126 resulted in an increased number of patterning events, supernumerary cusp formation, and increased Hoxa4 and Hoxb6 gene expression when compared to the controls. Together, these studies illustrate the profound effects of epigenetic regulatory events at all stages of the differentiation of craniofacial peripheral tissues from the neural crest, including lineage specification, tissue differentiation, and patterning.