Management of hepatocellular carcinoma (HCC) is a complex issue, as it needs to take into account the liver disease, the cancer stage and the performance status of the patient. The treatment decision has to be based on robust scientific evidence and for this it is instrumental to have a proper staging system linked to the treatment indication. The BCLC proposal serves these two purposes and has been validated worldwide and endorsed by several scientific associations. The sole systemic therapy that has shown efficacy in improving the survival of HCC patients is sorafenib, an oral kinase inhibitor that blocks the Raf/MEK/ERK pathway and the receptor for VEGFR 2 and PDGFR-beta. Sorafenib has been recognized as the standard of care for patients who cannot benefit from treatments of higher priority and established efficacy, such as surgical resection, transplantation, ablation and transarterial chemoembolization. Sorafenib has changed the management of HCC, opening the path to combination therapies for patients at advanced stages and to evaluation as an adjuvant for those in earlier evolutionary stages.