Abstract: Cetuximab is a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR) for the treatment of metastatic colorectal cancer (mCRC). However, most patients treated with cetuximab experience disease progression due to the development of secondary drug resistance, presenting a significant challenge in managing cetuximab therapy. Existing studies have found that cetuximab resistance mechanisms are not only linked to the RAS/RAF/PIK3CA genetic mutations but also closely associated with the abnormal activation of PI3K/AKT/mTOR, Wnt/β-catenin, c-MET/HGF, and RAS-MAPK signaling pathways. Additionally, HER2 and MET amplification, microsatellite instability, changes in tumor metabolism, and alterations in the tumor microenvironment may also contribute to cetuximab resistance in patients. This review focuses on the potential molecular mechanisms of cetuximab resistance in the treatment of mCRC, and provides new ideas for overcoming cetuximab resistance in clinic.