Wnt signalling has an important role in cell fate determination, tissue patterning and tumorigenesis 1, 2, 3, 4. Secreted antagonists of Wnt include Frizzled (Fz)-related proteins (FRPs) 5, 6, 7, Cerberus 8, Wnt inhibitory factor (WIF) 9 and Dickkopf (Dkk) 10, 11. FRPs, Cerberus and WIF have all been shown to act by binding and sequestering Wnt. We report a novel mechanism of Wnt-signalling inhibition by human Dkk-1. Dkk-1 demonstrated no interaction with Wnt but bound a single cell surface site with high affinity (K D= 0.39 nM). Its receptor was detectable in a complex with a relative molecular mass of 240,000 (M r 240K) with [125 I] Dkk-1 by covalent affinity cross-linking. Wnt signalling through β-catenin is mediated by the Fz receptor 12 and a recently identified low-density-lipoprotein-receptor-related co-receptor, LRP6/Arrow 13, 14, 15. Overproduction of the 200K LRP6 protein, but not of Fz, strikingly increased Dkk-1 binding as well as the amount of the 240K cross-linked complex, which was shown to be composed of Dkk-1 and LRP6. Moreover, Dkk-1 function was completely independent of Fz but LRP6 dramatically interfered with the Dkk-1 inhibition of Wnt signalling. Thus, unlike Wnt antagonists, which exert their effects by molecular mimicry of Fz 5, 6, 7 or Wnt sequestration through other mechanisms 8, 9, Dkk-1 specifically inhibits canonical Wnt signalling by binding to the LRP6 component of the receptor complex.