The quest for targetable molecules and pathways that can be manipulated to treat skeletal disease and restore bone health is perpetually evolving. Successful pharmacologic treatment of nearly all skeletal diseases among adults, and many pediatric skeletal diseases, requires a fundamental understanding of the influence that different signaling pathways exert on the bone remodeling cycle. Because pharmacologic agents that improve bone mass and fracture susceptibility can work by increasing [1] or by decreasing [2] bone turnover, it is clear that the effects of any agent on both resorptive and formation arms of the remodeling cycle are key to its success. Recently, a great deal of therapeutic interest has developed around the Wnt signaling pathway in light of the high bone mass phenotype observed among patients with certain mutations in Wnt-signaling-associated genes.