Cranial neural crest cells (CNC) are a transient population of “stem cells” that originate at the border of the neural plate and the epidermis and migrate ventrally to contribute to most of the facial structures including bones, cartilage, muscles and ganglia. ADAM13 is a cell surface metalloprotease that is essential for CNC migration. Here we show that a Wnt receptor, Fz4, binds to the cysteine rich domain of ADAM13 and negatively regulate its proteolytic activity in vivo. Gain of Fz4 function inhibit CNC migration and can be rescued by gain of ADAM13 function. Loss of Fz4 function also inhibits CNC migration and induces a reduction of mature ADAM13 together with an increase in the ADAM13 cytoplasmic fragment that is known to translocate in the nucleus to regulate gene expression. We propose that Fz4 associate with ADAM13 during transport to the plasma membrane to regulate its proteolytic activity.