Wnt growth factors control numerous cell fate decisions in development by altering specific gene expression patterns through the activity of heterodimeric transcriptional activators. These consist of beta-catenin and one of the four members of the T-cell factor (TCF) family of DNA-binding proteins. How can the Wnt/beta-catenin pathway control various sets of target genes in distinct cellular settings with such a limited number of nuclear effectors? Here we asked whether different TCF proteins could perform specific, nonredundant functions at natural beta-catenin/TCF-regulated promoters. We found that TCF4E but not LEF1 supported beta-catenin-dependent activation of the Cdx1 promoter, whereas LEF1 specifically activated the Siamois promoter. Deletion of a C-terminal domain of TCF4E prevented Cdx1 promoter induction. A chimeric protein consisting of LEF1 and the C terminus of TCF4E was fully functional. Therefore, the TCF4E C terminus harbors a promoter-specific transactivation domain. This domain influences the DNA binding properties of TCF4 and additionally mediates an interaction with the transcriptional coactivator p300. Apparently, the C terminus of TCF4E cooperates with beta-catenin and p300 to form a specialized transcription factor complex that specifically supports the activation of the Cdx1 promoter.