Several chemotherapeutical agents, alone or in combination, have been assessed in HCC. Regrettably, mainly due to the frequent association between HCC and cirrhosis, all these drugs have shown a limited efficacy and an inadmissible rate of adverse effects. Accordingly, standard chemotherapy is not recommended for HCC. Fortunately, in the last years we have been witness of important advancements in the knowledge of the disrupted molecular pathways associated with the cancer initiation and progression. This knowledge has allowed the development of new agents that specifically and selectively block the altered pathways, minimizing the frequent side effects associated with conventional therapies. Among them, the only one that up to date has shown benefits in term of survival is sorafenib, an oral available multikinase inhibitor that acts mainly inhibiting the tumor proliferation and the formation of new vessels, freezing the tumor growth. The positive results obtained with sorafenib in several clinical trials have justified that this agent has become the standard and widely accepted therapy in patients with advanced HCC. Furthermore, in 2016 a new drug, called Regorafenib, was approved for the treatment of hepatocellular carcinoma en second line after progression under sorafenib for those patients who are tolerant to sorafenib. There are other molecular targeted therapies under investigation in HCC, and in some of them, promising results in preliminary studies have been obtained. Consequently, it is highly recommended to participate in clinical trials that evaluate these novel agents. Undoubtedly, in the next years further treatment advancements will be in place that will allow improving the survival and the quality of life of patients affected with HCC.