Hepatocellular cancer (HCC) is the fifth most common malignancy worldwide and the third leading cause of cancer death. HCC is highly resistant to conventional systemic therapies and prognosis for advanced HCC patients remains poor. Identification of signalling pathways responsible for HCC growth and progression such as RAS/RAF/ MEK/ERK or PI3K/AKT/mTOR has determined molecular targets whose inhibition by novel agents may improve patients’ outcome. Based on a phase III clinical trial demonstrating a significant impact on overall survival, sorafenib has been approved for treatment of advanced HCC. Many other targeted agents – monoclonal antibodies, tyrosine kinase inhibitors and serine-threonine kinase inhibitors – have been tested in phase II clinical trials and have recently entered phase III studies. The aim of this article is to review molecular mechanisms responsible for development and progression of HCC, and the role of targeted therapies in the treatment of HCC which may soon be introduced into clinical practice.