Here, using isogenic CRC cell lines and Ehf /Cdx1 compound deletion mice we provide direct evidence that the ETS family transcription factor, EHF, and the caudal homeobox transcription factor, CDX1, co-operate to control the differentiation state of CRCs, and that their co-ordinate epigenetic silencing in a subset of poorly-differentiated CRCs drives colorectal tumour progression. Here, CDX1 is linked to colorectal carcinoma.