Molecular targeted therapy has become a new hot spot with the in-depth basic research on advanced biliary tract cancer (ABTC). Phase Ⅱ and Ⅲ trials of the molecular targeted therapies for ABTC are summarized to provide new insights into clinical practice. Phase II trials have shown that vascular endothelial growth factor receptor inhibitor and mitogen-activated protein kinase inhibitor do not exhibit good anti-tumor activity, but epidermal growth factor receptor (EGFR) inhibitor has proven to be safe and effective in the treatment of ABTC. The only multicenter, open-label, randomized, controlled phase Ⅲ trial has shown that nilotinib combined with gemcitabine and oxaliplatin, as the first-line chemotherapy for ABTC, cannot significantly increase the overall survival in patients. Subgroup analysis has shown that standard chemotherapy combined with nilotinib can significantly increase the progression-free survival in patients. These results indicate that EGFR inhibitor is effective to control the progression of ABTC, suggesting that EGFR might be a novel therapeutic target.