CRC is the fourth most frequently diagnosed tumor and the second leading cause of cancer death in the United States. KRAS mutations occur in 35-45% of metastatic-CRC and preclude responsiveness to cetuximab or panitumumab. However, less than 20% of KRAS wild-type (wt) patients achieve objective response. Alterations of BRAF/NRAS/ PIK3CA/PTEN, have independently been found to give rise to resistance. The first-line trials with cetuximab chemotherapy are conflicting, because of the many differences among prospective and retrospective evaluations. In neoadjuvant regimens, cetuximab with CT obtained a significant and early increase of the RR. In second-line studies cetuximab improved RR and PFS. In third-line studies cetuximab-irinotecan is associated with a significant advantage in ORR, mTTP and OS. Cetuximab has not reported any benefit neither in adjuvant nor in trials with bevacizumab. In third-line studies cetuximab-irinotecan is associated with a significant advantage in ORR, mTTP and OS. Value of KRAS is questioned, since a high percentage of KRAS-wt patients has no benefit with cetuximab. More and more data on the molecular patterns of these tumors underline their biological complexity. Cetuximab treatment is usually well tolerated. Moreover, toxicity seems to correlate with response to treatment. This patents review focuses on recent advances in the treatment of CRC with cetuximab including several novel therapeutic protocols of intervention.