While the biological roles of canonical Wnt/β-catenin signaling in development and disease are well documented, understanding the molecular logic underlying the functionally distinct nuclear transcriptional programs mediating the diverse functions of β-catenin remains a major challenge. Here, we report an unexpected strategy for β-catenin-dependent regulation of cell-lineage determination based on interactions between β-catenin and a specific homeodomain factor, Prop1, rather than Lef/Tcfs. β-catenin acts as a binary switch to simultaneously activate expression of the critical lineage-determining transcription factor, Pit1, and to repress the gene encoding the lineage-inhibiting transcription factor, Hesx1, acting via TLE/Reptin/HDAC1 corepressor complexes. The strategy of functionally distinct actions of a homeodomain factor in response to Wnt signaling is suggested to be prototypic of a widely used mechanism for generating diverse cell types from pluripotent precursor cells in response to common signaling pathways during organogenesis.