Medical therapies have entered center stage in the treatment of hepatocellular carcinoma (HCC) little more than a year after the positive results of a large phase III trial of sorafenib showed a clear survival benefit with sorafenib, a targeted agent, in this setting. Even though this marks a breakthrough in the treatment of HCC, the narrow patient profile necessary for the study to be successful has generated a number of questions regarding the efficacy of this approach in other clinical settings. New studies aiming to define the role of sorafenib from in the adjuvant setting, through patients with more advanced liver disease, all the way to combination treatments of HCC have been initiated. The success of one targeted drug has stimulated enormously the efforts of competitors to develop additional and better drugs, either in a first-line or a second-line setting. These are exciting times for the treatment of HCC, both for physicians and patients. In the years to come we will see an extension of treatment options in different clinical situations in patients with HCC, and survival will be improved in many stages of the disease, except for the most advanced. The rapid increase in knowledge about the molecular mechanisms underlying the development and progression of HCC will lead to a more tailored approach to treatment depending on the molecular characteristics of the tumor and the disease stage.