Numerous studies in chordates and arthropods currently indicate that Cdx proteins have a major ancestral role in the organization of post-head tissues. In urochordate embryos, Cdx loss-of-function has notably been shown to impair axial elongation, neural tube (NT) closure and pigment cell development. Intriguingly, in contrast to axial elongation and NT closure, a Cdx role in neural crest (NC)-derived melanocyte/pigment cell development has not been reported in any other chordate species. To address this, we generated a new conditional pan-Cdx functional knockdown mouse model that allows circumventing Cdx functional redundancy as well as the early embryonic lethality of Cdx mutants. Through directed inhibition in the neuroectoderm, we here provide in vivo evidence that murine Cdx proteins impact melanocyte and enteric nervous system development via, at least in part, directly controlling the expression of the key early regulators of NC ontogenesis Pax3, Msx1 and FoxD3. Our work thus reveals a novel role for the Cdx proteins atop of the trunk NC-gene regulatory network in the mouse, which appears to be inherited from their ancestral orthologue.