The Grainyhead-like (Grhl) family are highly-conserved transcription factors that regulate multiple stages of embryogenesis, including skin barrier formation, neural tube closure and craniofacial development. Loss of family member grhl3 in zebrafish, and Grhl2 in mouse, leads to defects in the patterning, establishment and growth of the craniofacial skeleton, and my group is interested in delineating both the downstream target genes and upstream regulatory factors of Grhl2 in this context. Through analysis of a customised database of putative target genes, RNA-Seq, ChIP and ex vivo explant analyses, we show that the soluble morphogen Noggin, an antagonist of the BMP pathway, is a novel target of Grhl2. Furthermore, using in silico and in utero expression analyses and functional deletion in mice, we have identified a novel 2.4kb enhancer element (mm1286) that regulates Grhl2 expression at the mRNA level, and augments Grhl2-mediated transcriptional control of craniofacial development. Deletion of this genomic element, in the context of loss of one allele of Grhl2 (through generation of double heterozygous mm1286+/-;Grhl2+/- mice), results in a significant predisposition to palatal clefting at birth. Moreover, we found that a highly conserved 325 bp region of this enhancer element is both necessary and sufficient for mediating the craniofacial-specific enhancing activity of this region, and that an ultra-conserved 12-base pair sequence (CTGTCAAACAGGT) is essential for enhancer function within the craniofacial region. Together, these data provide valuable new insights into the role of Grhl2 in the over-arching control of craniofacial development.