Colorectal cancer (CRC) is the second most common cancer in Western Europe. Combinations of oxaliplatin or irinotecan with fluorouracil have increased responses in first-line therapy up to 40%, but prognosis is still poor. Almost 80% of patients will progress during the first year of treatment and usually become refractory to all current therapies, including EGFR inhibitors. The likelihood of achieving a response to cetuximab-based therapy is not related to overt levels of epidermal growth factor receptor (EGFR) expression in the tumor. Whilst other markers of cetuximab activity, such as phosphorylation status of the EGFR, quantification of ligands and polymorphisms in the promoter or in first intronic region, have not been validated, response rate correlates with the intensity of patient skin reaction. Such a relationship is not as clear as with other anti EGFR therapies, such as the EGFR-specific tyrosine kinase inhibitor, gefitinib, where efficacy appears to correlate with mutations in the cytoplasmic domain of the receptor. Recently, EGFR mutations have been evaluated in CRC and were shown to occur at a very low frequency ( < 0.5%), supporting that, mutations on the EGFR gene, cannot explain cetuximab efficacy in irinotecan-refractory patients. We will review the current on-going EGFR inhibitor trials and discuss alternative pathways to EGFR, which can help to explain cetuximab resistance in CRC.