Wnt and Hedgehog (Hh) signaling pathways instruct cells to differentiate and adopt new fates. These pathways depend on proteins encoded by multigene families and their activation is a lifelong necessity. Unfortunately, inadvertent activation leads to a host of diseases. There are 19 mammalian Wnts, which participate in canonical signaling involving nuclear translocation of β-catenin, or non-canonical signaling including the planar cell polarity and G-protein/Ca2+pathways. Mutations in any one Wnt or in those encoding a component within the pathway(s) lead to birth defects and diseases. The same is true for Hh signaling, of which there are 3 homologues in mammals. Unlike Wnts, however, each homologue signals through similar downstream components. Hh signaling to responding cells can lead to epithelial-to-mesenchymal transitions involved in normal embryonic pattern formation and in cancer metastasis. How this crosstalk between Wnt and Hh signaling leads to the differentiation of extraembryonic endoderm in the mouse embryo is the primary focus in the Kelly Lab, and elucidating how this occurs under normal conditions has led to a better understanding of what goes wrong when cells metastasize, colonize and form tumours elsewhere in the body.