The recent introduction of targeted therapies in the treatment of patients with metastatic colorectal cancer (mCRC) not only improved efficacy but also toxicity and costs of the therapy, therefore requiring the identification of decision-making tools to select patients who are likely to benefit from them. By now, several studies have demonstrated an association between epidermal growth factor receptor (EGFR) non-increased gene copy number, evaluated by fluorescence in situ hybridization (FISH), and resistance to the treatment with antiEGFR monoclonal antibodies (moAbs) in patients with mCRC. However, the reproducibility of data by standardization of methods still remains an obstacle to be faced for clinical application of the test. We present a review of studies pertaining EGFR FISH analysis as a predictive test of clinical outcome to the treatment with antiEGFR moAbs in mCRC to point out the existing knowledge and the open questions about this issue.