Frontonasal dysplasia (FND) refers to a class of midline facial malformations caused by abnormal development of the facial primordia. The term encompasses a spectrum of severities but characteristic features include combinations of ocular hypertelorism, malformations of the nose and forehead and clefting of the facial midline. Several recent studies have drawn attention to the importance of Alx homeobox transcription factors during craniofacial development. Most notably, loss of Alx1 has devastating consequences resulting in severe orofacial clefting and extreme microphthalmia. In contrast, mutations of Alx3 or Alx4 cause milder forms of FND. Whilst Alx1, Alx3 and Alx4 are all known to be expressed in the facial mesenchyme of vertebrate embryos, little is known about the function of these proteins during development. Here, we report the establishment of a zebrafish model of Alx-related FND. Morpholino knock-down of zebrafish alx1 expression causes a profound craniofacial phenotype including loss of the facial cartilages and defective ocular development. We demonstrate for the first time that Alx1 plays a crucial role in regulating the migration of cranial neural crest (CNC) cells into the frontonasal primordia. Abnormal neural crest migration is coincident with aberrant expression of foxd3 and sox10, two genes previously suggested to play key roles during neural crest development, including migration, differentiation and the maintenance of progenitor cells. This novel function is specific to Alx1, and likely explains the marked clinical severity of Alx1 mutation within the spectrum of Alx-related FND.