In this review, we discuss the mounting evidence supporting EGFR ligands epiregulin (EREG) and amphiregulin (AREG), which are overexpressed in CRC with potential key roles in tumor progression, as predictive biomarkers for EGFR-targeted therapy sensitivity as well as mediators of therapy resistance; though further studies are necessary to validate the prognostic roles and mechanisms by which these ligands contribute to resistance. Here, AREG is linked to colorectal carcinoma.