Hepatocellular carcinoma (HCC) is a severe form of liver cancer that is found worldwide. Treatments such as liver transplantation and surgical resection and local-regional therapies such as transarterial chemoembolization have progressed considerably and play a prominent role in HCC management. After those treatments, though, systematic drug intervention is required to deal with tumor metastasis in its early stages and the high frequency of tumor recurrence and/or metastasis. The approval of sorafenib, an agent that targets receptor tyrosine kinases (RTKs), as the first effective drug for systemic treatment of HCC represents a milestone in the treatment of this disease. In addition to sorafenib, a number of agents that target various RTKs or intracellular signal transduction molecules, such as mTOR, are currently being investigated as monotherapy or combination therapy for HCC. This article reviews advances in the study of molecularly targeted agents to treat HCC.