•Metastatic colorectal cancer (mCRC) remains a leading cause of cancer-related morbidity and mortality•Amplification of the HER2 gene is the latest molecular subset to be therapeutically targetable in this disease•HER2 amplifications and/or mutations are clinically implicated in primary and acquired resistance to anti-EGFR therapy•Many phase I/II studies investigating HER2 targeting with trastuzumab based therapy have demonstrated encouraging results•Despite promising results, the frequency of HER2 amplification in mCRC is low, and therapeutic advances are unlikely to be rapid Despite recent advances in the treatment of metastatic colorectal cancer (mCRC), 5 years survival rates remain low. Chemotherapy remains as the mainstay of treatment with only few available targeted therapies. Human epidermal growth factor receptor 2 (HER2) amplification occurs in approximately 5% of metastatic colorectal cancer and it has been studied as a mechanism of resistance for anti-epidermal growth factor receptor (EGFR) therapy. Furthermore, several studies such as HERACLES-A, MyPathway and the DESTINY-CRC01 trials have shown significant clinical benefit of HER2 blockade in patients with HER2 amplified mCRC. In this review, we provide an overview of the clinicopathological features of HER2 amplification and mutations in mCRC. In addition, we review HER2 as a biomarker of intrinsic and acquired anti-EGFR resistance as well as the preclinical, clinical and translational studies investigating the use of HER2 targeted therapies and future studies.