This review integrates three interconnected regulatory layers, i.e., (1) ZEB1's direct epigenetic control of target gene expression via histone modification and DNA methylation, (2) post-transcriptional regulation of ZEB1 itself by ncRNAs (miRNAs, circRNAs, and lncRNAs) that create feedback circuits modulating layer 1, and (3) upstream modulation of ZEB1 transcriptional activity by oncogenic signaling pathways (Wnt/β-catenin, TGF-β, NF-κB, MEK-ERK, JAK/STAT3, and HIF-1α) to provide a comprehensive picture of ZEB1 in CRC metastasis and its therapeutic implications. This evidence concerns the gene HIF1A and colorectal carcinoma.