Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The major etiologies and risk factors for development of HCC are well defined and some steps of hepatocellular carcinogenesis have been elucidated. Despite these scientific advances and the implementation of measures for early detection of HCC in patients who are at risk of this disease, survival of patients has not improved greatly over the past three decades. This situation is partly due to the limited therapeutic options available. While surgery and percutaneous or transarterial interventions are effective for patients with limited or compensated underlying liver disease, more than 80% of patients present with multifocal HCC and/or advanced liver disease, or have comorbidities at the time of diagnosis. Treatment options for these patients have previously been limited to best supportive care. The effectiveness of targeted therapy with monoclonal antibodies or small-molecule kinase inhibitors has now been demonstrated for the treatment of different tumors. In 2007, the multitargeted kinase inhibitor, sorafenib, was found to prolong survival significantly for patients with advanced HCC. This Review discusses the mechanisms of targeted therapies and clinical studies that have investigated these therapies in patients with HCC. Perspectives for future developments are also provided.