Wnt signal transduction is crucial for maintaining the balance between proliferation and differentiation throughout embryogenesis and postnatal life. Here, we provide a comprehensive overview of the conventional knockout mouse studies of both the canonical and the noncanonical Wnt pathways during mammalian development. Many of these knockout mice display early embryonic lethality, underscoring the fundamental importance of Wnt signal transduction, but precluding functional analyses at later stages. Use of conditional or inducible mouse models will enable us to study the role of Wnt signaling during later stages of development and adult life. Furthermore, genomic-scale approaches and advanced imaging techniques could provide a means to start dissecting the mechanism behind the observed phenotypes.