Conventional systemic chemotherapy has been developed with so-called anti-cancer agents, essentially screened for cytotoxicity to cultured cancer cells. However, in patients with hepatocellular carcinoma (HCC), the role of chemotherapy is quite limited because most anti-cancer agents are ineffective and relatively toxic to HCC patients with chronic liver diseases. On the other hand, accumulated understanding of the molecular mechanisms regulating cancer progression has led to novel development of molecularly targeted therapies with cytostatic agents. Recently, a phase III clinical trial revealed a multi-kinase inhibitor, Sorafenib, as the first agent leading to improved overall survival of patients with advanced HCC. A new era of HCC treatment has arrived, based on identification of deranged signaling pathways of cancer cells or their microenvironment. This review summarizes the molecular hallmarks of HCC with a focus on angiogenesis, growth signals, and mitotic stress, and a novel concept "synthetic lethality" for the targeted therapy strategy.