Several studies have shown that human epidermal growth factor receptor 2 (HER2) amplification could be a predictive biomarker of resistance to anti-epidermal growth factor receptor monoclonal antibodies in patients with RAS wild-type metastatic colorectal cancer (mCRC). Dual HER2 inhibition with trastuzumab plus lapatinib or pertuzumab has shown promising preliminary anti-tumoral efficacy in RAS wild-type mCRC. HER2-targeted therapeutic strategies have the potential to change the treatment paradigm for a clinically relevant subgroup of patients with mCRC.