Metastatic colorectal cancer (mCRC) continues to be counted as a major health problem. The introduction of newer cytotoxics, irinotecan and oxaliplatin, has achieved a significant improvement in survival rates.Novel targeted therapies (bevacizumab, and cetuximab) in combination with most efficient chemotherapy regimens have pushed the median survival beyond the 2-year mark and increased the proportion of patients which could benefit from resection of metastatic lesions.In addition, everal studies have proved that the CRC mutation profiles should influence patient selection or stratification in prospective trials. KRAS mutational status represents a paradigm for biomarker development in the era of molecular targeted herapies. The present article is an overview of the most important studies in the development of biomarkers for the optimization of antiepidermal growth factor receptor (anti-EGFR) treatment in mCRC, beyond KRAS mutations, which is a work in progress. The aim will be to identify molecular markers that might be used to select patients with a higher probability of response to anti-EGFR monoclonal antibodies.Overall the accumulating vidence of the molecular biology of CRC has substantially changed the approach to mCRC treatment and has given clinicians more ational options for treating this illness.