With the growth of research on hepatobiliary cancers, great progress has been achieved in the development of drugs targeting the abnormal pathways or molecules in cancer cells. At present, the drugs targeting the epidermal growth factor receptor (EGFR) has been widely used in hepatobiliary cancer therapy, and has exhibited unique advantages compared to traditional chemotherapy drugs, but may still give rise to drug resistance in long term use. This paper mainly addresses the clinical application of EGFR-targeted therapy in hepatobiliary cancers and the mechanisms of resistance, with the purpose of providing new insights for clinical practice.