The recent advances in the understanding of the mechanisms underlying HCC development and progression have allowed molecularly targeted agents to enter the treatment options for HCC. The advent of sorafenib has shown that molecularly targeted agents can effectively impact survival in patients with HCC and their side effects can be managed even in patients with cirrhosis. Notwithstanding the survival advantage offered by sorafenib, a great margin of improvement may be envisaged particularly for nonresponders, as well as for those patients who experience escape from treatment efficacy. In the recent years, a large number of new molecularly targeted agents have been investigated and are currently under investigation for the treatment of HCC. These drugs represent new tools for the management of advanced HCCs that, otherwise, would be orphan of effective options.