Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and its incidence is still increasing. While the primary curative treatment for HCC is surgical resection, a major obstacle for the treatment of HCC is the high frequency of tumor recurrence even after curative resection. Effective palliative treatment is hindered by the evidence that HCC is frequently resistant to conventional chemotherapy and radiotherapy. Targeted therapy which specifically inhibits molecular abnormalities has emerged as a novel approach for the innovative and effective medical treatment of malignancies. In order to fulfill this promise there is an urgent need to identify the optimal targets for the treatment of HCC. A multi-kinase angiogenesis inhibitor, sorafenib, has been revealed as the first agent to show favorable overall survival in patients with advanced HCC. A new era of HCC treatment has arrived, but there has been limited improvement in survival benefits with the status quo. This review summarizes molecular targeted therapy for HCC, with a focus on angiogenesis, growth signaling, and mitosis, as well as a promising concept, "cancer stemness" for the current and potential next strategies of HCC treatment.