Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. Despite treatment advancements in the last decades, CRC remains heterogeneous with significant clinical and genetic diversity. Human epidermal growth factor receptor 2 (HER2) proto-oncogene plays a critical role, as its amplification or overexpression leading to abnormal cell proliferation and tumorigenesis. HER2 overexpression or amplification is identified in 2-4% of metastatic CRCs (mCRC) patients, representing a potential therapeutic target. It is also associated with resistance against epidermal growth factor receptor (EGFR)-targeted therapies like cetuximab and panitumumab, for treatment of RAS wild-type mCRC. Although HER2-positive mCRC is rare, assessing HER2 levels is important. Furthermore, anti-HER2 therapies exhibited non-toxic profile and high efficacy in chemorefractory cases. This review delves into modern management of anti-HER2 therapies in CRC with a particular focus on recent advances and current knowledge about the prognostic and predictive value of HER2.