Nowadays, targeting epidermal growth factor-receptor (EGFR) represents an additional therapeutic line for patients with metastatic colorectal cancer (MCRC). Cetuximab, the first available anti-EGFR monoclonal antibody, is approved, combined to irinotecan, in EGFR-positive MCRC after progression while under an irinotecan-based chemotherapy. Other anti-EGFR monoclonal antibodies (panitunumab, matuzumab) are currently evaluated. Preliminary data seem to indicate similar efficacy and toxicity profile to that of cetuximab. Orally available EGFR tyrosine kinase inhibitors (gefitinib, erlotinib, EKB 569) have also been evaluated in patients with MCRC. Preliminary data in terms of clinical activity are not favouring their combination to conventional chemotherapy. Furthermore, they seem to increase the rate of severe haematological and digestive toxicities, especially in patients previously exposed to chemotherapy. At this point of the clinical development of these all EGFR inhibitors (monoclonal antibodies or tyrosine kinase inhibitors) in MCRC, informative data from randomized studies are urgently needed.