Most patients with hepatocellular carcinoma (HCC) lose the opportunity for radical treatment due to the insidious onset of HCC, thus chemotherapy plays an important role in treatment of HCC at middle and advanced stage. The etiology for and the molecular pathways involved in HCC have been further understood with the development of genetic knowledge and molecular biology, which provide the biological rationale for targeted therapy. In more than 10 recent years, some advances have been achieved in targeted drugs for HCC, and sorafenib has already been approved by FDA for advanced HCC, while the results of other clinical trials of targeted drugs are less than satisfactory, and the research of targeted drugs for HCC seems to enter a stagnant state. Here, the authors discuss the current advances in targeted therapy for HCC and analyze the causes for the failure of many clinical trials as well as the potential solutions.