According to the American Cancer Society, colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Early detection efforts have reduced mortality, yet approximately 50,000 deaths are expected this year. Much of the etiology underlying CRC remains unclear, which hampers efforts to design more efficacious therapies. As such, a strong need exists to better understand the molecular mechanisms governing CRC progression. One of the first targets for molecular targeted therapies was the tyrosine kinase receptor epidermal growth factor receptor (EGFR). Preclinical studies in our lab and others showed that targeting EGFR greatly reduced incidence of CRC in mouse models. However, subsequent clinical trials using EGFR inhibitors were less efficacious, suggesting that targeting EGFR alone does not result in a significant benefit in most CRC cases. Mutations in Kras can explain some non-responding CRCs, but even in cancers lacking Kras mutations, little is known about which cancers are likely to respond. In this study, we used intestine-specific genetic ablation of Egfr in the ApcMin/+ (genetic) and axozymethane (carcinogenic) CRC mouse models. We discovered that 10% of colonic tumors arise independent of EGFR activity. By molecular analysis we confirmed the absence of Egfr in these tumors, and conclusively demonstrated the existence of an EGFR-independent mechanism by which CRC can arise and progress. Residual tumors lacking EGFR were larger in size than those developing under normal EGFR activity, suggesting these cancers may be a more aggressive form of CRC. We also have evidence that ERBB3, a related EGF receptor, mediates compensatory and alternative pathways, suggesting an important role of ERBB3 may be in EGFR-independent CRC progression. Furthermore, we have generated an additional model that conditionally inactivates ERBB3 (Erbb3tm1Dwt/Erbb3tm1Dwt), and when combined with Egfrtm1Dwt/Egfrtm1Dwt>, these mice will have EGFR and ERBB3 combined deficiency in the intestinal epithelia. The innovative models we developed will provide powerful tools to genetically dissect molecular pathways contributing to CRC, leading to novel targets and associated biomarkers for therapeutic intervention. The study will advance our understanding of EGFR biology during colonic tumorigenesis, ultimately contributing to better therapies for CRC.