Wnt genes encode secreted proteins which are implicated in receptor-mediated cell-cell signaling events important in embryogenesis, but the second messenger systems modulated by Wnts have not been identified. We report that ectopic expression of Xwnt-5A in zebrafish embryos enhances the frequency of intracellular Ca2+ transients in the enveloping layer of the blastodisc, whereas Xwnt-8 does not. These transients are independent of extracellular Ca2+. Consistent with the observed Ca2+ transients playing a role in responses of embryos to Xwnt-5A, we report that the ligand-activated serotonin type 1C receptor, which stimulates PI cycle activity and Ca2+ signaling independent of Wnts, phenocopies embryonic responses to Xwnt-5A. These results suggest that intercellular signaling by a subset of vertebrate Wnts involves modulation of a intracellular Ca2+ signaling pathway, which may arise from phosphatidylinositol cycle activity.