Mutations in APC or β-catenin inappropriately activate the transcription factor Tcf4, thereby transforming intestinal epithelial cells. Here it is shown that one of the target genes of Tcf4 in epithelial cells is Tcf1. The most abundant Tcf1 isoforms lack a β-catenin interaction domain. Tcf1 ^−/−mice develop adenomas in the gut and mammary glands. Introduction of a mutant APC allele into these mice substantially increases the number of these adenomas. Tcf1 may act as a feedback repressor of β-catenin–Tcf4 target genes and thus may cooperate with APC to suppress malignant transformation of epithelial cells.