Abstract: The development of anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR McAbs) marked a significant milestone in metastatic colorectal cancer (mCRC) treatment. The addition of anti-EGFR McAb can greatly improve quality of life of mCRC patients and mCRC prognosis and markedly increases the overall survival rate from 6 months to nearly 30 months. KRAS and NRAS mutations contribute to the primary resistance to anti-EGFR therapy and can serve as well-established predictive markers for patient selection. Apart from the RAS family, other molecular alteration in EGFR signaling pathway may also compromise the efficacy of anti-EGFR treatment. In addition, patients who responded to anti-EGFR treatment eventually develop acquired drug resistance within 13 and 18 months. In this review, the mechanisms underlying the primary and secondary resistance to anti-EGFR therapy are summarized, and a possible strategy to circumvent drug resistance is proposed. We hope this review can provide compelling evidence, deeper insights, and reasonable guidance to facilitate the precise molecular targeted therapy of mCRC.