Anti-EGFR antibodies(cetuximab and panitumumab)are molecular targeted agents that exert their antitumor effects by binding directly to the epidermal growth factor receptor(EGFR)and inhibiting its downstream signaling. Anti-EGFR antibodies have become one of the most important agents in the treatment of metastatic colorectal cancer(CRC), showing efficacy in combination with cytotoxic chemotherapeutic agents and as single agents in first-line and second-line treatment or later. Molecular targeted agents show more potent therapeutic effects than conventional chemotherapeutic agents, but their cost-effectiveness is often an issue due to their high drug costs. Predictive biomarkers of therapeutic efficacy that enable appropriate patient selection have an important role not only in improving the cost-effectiveness of molecular targeted agents, but also from the perspective of avoiding side effects in invalid patients. In addition to RAS and BRAF genotypes as molecular biological factors, anatomical factors such as the site of primary tumor(sidedness)are described in guidelines as important biomarkers for anti-EGFR treatment in the treatment of metastatic CRC. Recently, an association between HER2 gene amplification and anti-EGFR antibody resistance in RAS/BRAF wild-type metastatic CRC was reported. Furthermore, an epigenetic factor, DNA methylation status, was reported to be associated with the therapeutic effect of anti-EGFR treatments, and our subsequent studies have suggested that DNA methylation status is predictive of therapeutic efficacy of anti- EGFR antibodies regardless of the site of the primary tumor. Novel biomarkers will continue to be developed from a variety of approaches to provide more optimal cancer treatment for each individual patient.