The targeting of EGF receptors (EGFRs) in metastatic colorectal cancer has improved the outcome of patients with KRAS wild-type tumors. However, these improvements have been modest and do not translate across all patients with KRAS wild-type tumors. Better understanding of the EGFR pathway has led to the exploration of variable novel potential biomarkers of resistance and response to anti-EGFR therapy. This manuscript will focus on recently identified mechanisms of resistance to anti-EGFR therapy in KRAS wild-type colorectal cancer. Subsequently, an assessment will be presented on how the current understanding of some of these mechanisms of resistance has led, and will lead, to novel therapeutic opportunities in the management of colorectal cancer.