The mortality of hepatobiliary cancer still stays high around the world, with disappointing treatment status at advanced stage. Genomic analysis has identified the global spectrum of alterations in liver cancer, but the most common mutations are not actionable, meanwhile lacking potent molecular-targeted drugs for specific oncogenic drivers. Multiple-targeted drugs which mainly inhibited tumors' angiogenesis, such as sorafenib and lenvatinib, improved survival time for patients with advanced hepatocellular carcinoma, although the median overall survival remains 1-1.5 years. It is still ambiguous for the precise biomarkers of multiple-targeted drugs utilized in hepatobiliary cancer. Herein, we reported two observational patients who were sequentially treated by various targeted drugs and obtained lasting overall survival time. Both the two patients weekly switched targeted drugs according to the changes of tumor markers. These two cases would get us thinking: what is the underlying mechanism of molecular-targeted drugs in hepatobiliary tumors; and whether a "drugs screening model" during real-time treatment could be achieved through the assistance from sensitive and specific tumor markers.