Colorectal cancer is the third cause of cancer in the world. The recommended treatment of early stage (stage I and stage II) colorectal cancer is surgical removal, while the management of late stage (stage III and stage IV) colorectal cancer relies heavily on chemotherapy. Optimization of dosing and scheduling of chemotherapy agents are developed to improve response and survival rate of patients. Meanwhile, the rational targeting of molecular signaling pathways that are involved in the etiology of malignancies is currently one of the most promising strategies in novel anticancer drug development. Since first discovery of EGFR in 1962, EGFR family and its downstream signaling has become one of the most well characterized receptor tyrosine kinase system. In addition to their function in normal development, aberrant expression of EGFR is involved in abnormal cell proliferation, reduced apoptosis, cell migration, metastasis, angiogenesis and resistance to radiation and chemotherapy in cancer patients. Owing to the important role that EGFR plays in tumorigenesis, new classes of drugs that target EGFR, such as cetuximab, are among the most clinically advanced molecular-targeted therapies. The combination of EGFR monoclonal antibody with chemotherapy has shown efficacy in colorectal cancer treatment. However, the resistance of EGFR target therapy was recently observed due to complicated and different drug resistance mechanisms. Take EGFR monoclonal antibody, cetuximab, as an example, the response rate of cetuximab-plus-irinotecan therapy was about 23%. Some studies showed the resistance of EGFR to cetuximab is related to constitutive activation of mutant KRAS. However, more and more studies showed not all wild type KRAS patients response to cetuximab, while not all mutant Kras patients are refractory to cetuximab. These observations make it urgent to investigate the potential EGFR regulation mechanisms that may influence and predict the cetuximab response.