Accumulated understanding of the molecular pathways regulating cancer progression has led to the development of novel targeted therapies. Hepatocellular carcinoma (HCC) remains a highly lethal disease that is resistant to conventional cytotoxic chemotherapy and radiotherapy. Unlike conventional chemotherapy, molecular-targeted agents offer the potential advantages of a relatively high therapeutic window and use in combination with other anticancer strategies without overlapping toxicity. It is hoped that these drugs will become valuable therapeutic tools within the multimodal approach to treating cancer. A recent clinical trial revealed an oral multikinase inhibitor, sorafenib, as the first agent that has demonstrated improved overall survival in patients with advanced HCC. The present review summarizes molecular abnormalities of HCC with a focus on clinical studies, and current status as well as problems of the targeted strategies for HCC.