This work shows that the Wnt target gene CD44 acts as a positive Wnt-signaling regulator. Silencing CD44 expression decreases, whereas CD44 over-expression increases Wnt activity. CD44 functions at the level of the Wnt receptor LRP6. CD44 complexes with LRP6 upon Wnt treatment and modulates LRP6 membrane localization. Moreover, CD44 regulates Wnt signaling in the developing CNS of X. laevis embryos shown by a decreased expression of Wnt targets tcf-4 and en-2 in CD44 morphants.