The epidermal growth factor receptor is a member of the receptor tyrosine kinase family whose members play a critical role in oncogenesis. In particular, EGFR has been shown to participate in colon cancer development. Due to its role in the progression of colon cancer, EGFR has become an attractive target for therapy and two different classes of biologic agents have been evaluated: the EGFR monoclonal antibodies and the tyrosine kinase inhibitors. These two groups of agents differ in the specific molecular site which they target on the EGFR and in their efficacy in the treatment of colon cancer. This review will discuss the EGFR's evolving role as a prognostic and predictive biomarker in colon cancer. Once thought to be an inherent predictive factor for anti-EGFR monoclonal antibodies (MAbs) the EGFR has been replaced by KRAS and to some extent BRAF. The efficacy of both anti-EGFR MAbs, cetuximab and panitumumab, has been clearly demonstrated to depend upon the KRAS mutational status. The anti-EGFR monoclonal antibodies and their predictive biomarkers have taken colon cancer treatment another step closer towards the goal of tailored cancer therapy.