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Amplification of the HER2 gene is an indicator of poor prognosis for several kinds of malignancies such as breast and gastric cancer, and anti-HER2 targeting therapies provide clinical benefits in these patients. In 2011, HER2 was identified as a resistance molecule for de novo and secondary anti-epidermal growth factor receptor (EGFR) antibody therapy. HER2 activation provides a bypass signaling pathway after anti-EGFR antibody treatment of colorectal cancer. Cell line-based screening revealed that HER2 genomic amplification induces resistance to the anti-EGFR antibody cetuximab in colorectal cancer. Recently, HER2 itself has been recognized as a target for oncotherapy in colorectal cancer. The first part of this review provides an update on the present state of knowledge about the role of HER2 in colorectal cancer, including its prognostic relevance and role in resistance to anti-EGFR antibody treatment. In the second part of the review, we discuss the results of preclinical and clinical studies that examined the potential utility of anti-HER2 targeted therapy in colorectal cancer. Although it acts as a barrier for other molecular targeting agents such as cetuximab, HER2 itself is a promising target for oncotherapy. Current research indicates that anti-HER2 drugs will be developed further and introduced into clinical practice for the treatment of patients with HER2-positive colorectal cancer.