Understanding the mechanism of hepatocarcinogenesis has provided the opportunity to evaluate the efficacy of molecularly targeted agents in HCC. Sorafenib is a multikinase inhibitor with antiangiogenic, proapoptotic, and Raf kinase inhibitory effects, and it is the first new agent to consistently prolong overall survival in patients with advanced hepatocellular carcinoma (HCC). The success of sorafenib is a milestone for systemic therapy of HCC, shifting the paradigm of systemic treatment to molecular targeted agents. Many novel agents that inhibit angiogenesis, epidermal growth factor receptor, and mammalian target of rapamycin are under clinical development. This review attempts to summarize the current status and future perspectives of systemic therapy in HCC.