The purpose of this review is to provide a better understanding for the LRP co-receptor-mediated Wnt pathway signaling. Using proteomics, we have also subdivided the LRP receptor family into six sub-families, encompassing the twelve family members. This review includes a discussion of proteins containing a cystine-knot protein motif (i.e., Sclerostin, Dan, Sostdc1, Vwf, Norrin, Pdgf, Mucin) and discusses how this motif plays a role in mediating Wnt signaling through interactions with LRP. Developmental Dynamics 239:102–114, 2010. © 2009 Wiley-Liss, Inc.