Eph receptors and their ephrin ligands mediate cell repulsion during embryonic development. In the intestinal epithelium, EphB receptors are Wnt signaling target genes that control cell compartmentalization along the crypt axis. Recent findings have shown that this family of receptors are key players during colorectal cancer progression. Here, we review the current knowledge of the EphB/ephrinB system in the intestinal epithelium and we discuss their tumor suppressor role in the context of the multistep progression of colorectal cancer.