Wnt signalling pathways have been the focus of intense research activity for decades due to
their fundamental role in skeletal and dental development. Wntless, an exclusive chaperone
protein for the exocytotis of Wnt ligands, was identified in 2006. In the last decade, the molecular
biological studies of Wntless and its genetic studies in human and mice have highlighted the
importance of this protein in mineralised tissues, including bone, cartilage and teeth. This article
reviews recent developments and discrepancies in the role of Wntless in skeletal and dental
development based on mutant phenotypes, as well as the underlying mechanism involved in its
molecular and physiological regulation. We conclude that, though some controversial phenotypes
exist due to different Cre line resources, Cre recombinase activity and detection time
points, Wntless undeniably exerts a context- and stage-dependent regulatory function during
the development and homeostasis of both skeletal and dental tissue.