Signalling pathways that emerge from EGFR activation are critical in colon cancer (CC) biology. Its targeting with specific drugs has opened a new window in the treatment of this disease. In this regard, monoclonal antibodies (mAb) have evidenced a high degree of efficiency opposed to the uselessness of tyrosine-kinase inhibitors. Cetuximab is the mAb that has evidenced most activity in CC. After its initial approval as an irinotecan-resistance reversal agent, cetuximab has demonstrated its efficiency from the first line to heavily pretreated patients. In the first line, its addition may increase response rate to chemotherapy, improving liver metastases resection rate. Another promising approach has been suggested from combination schedules with bevacizumab. Panitumumab has been recently approved for CC. Although there is limited clinical experience, the latest data have confirmed its activity in heavily pretreated patients resulting in a clinical benefit vs. best support care. In spite of the clinical benefits, adverse events and the high sanitary cost derived from these drugs force the selection of patients with the highest probability of benefit. At the moment, when EGFR expression evidenced by immunohistochemistry has no value, skin toxicity and, fundamentally, K-Ras mutations may hint at critical information for confirmatory prospective studies.