Using human samples of primary CRC with BRAF mutations, CRC-established cell lines, transgenic mouse models for KrasG12D and BrafV600E intestinal tumors, and a Zeb1-deficient mouse, we found that ZEB1 is a tumor-promoting factor and induces an EMT phenotype in mouse Kras-mutant CRCs but, surprisingly, ZEB1 inhibits the EMT reprogramming of cancer cells and functions as a tumor suppressor in Braf-mutant CRCs. This evidence concerns the gene ZEB1 and cancer.