The incidence of hepatocellular carcinoma (HCC) has been rising in several western low-incidence areas over the past decade. The purpose of this review was to summarize the current knowledge on the 'state of the art' management of HCC focusing on targeted systemic therapies. The information for this review was compiled by searching the PubMed and MEDLINE databases for articles published until 1 June 2012. Cytotoxic chemotherapy has failed to affect outcome of HCC. Treatment with sorafenib is associated with survival gain in HCC but the responses are not durable. In addition, sorafenib is associated with substantial dermatologic and gastrointestinal toxicity. In this review, the authors summarize molecular targets and signal transduction pathways in HCC and provide an update of published and ongoing studies. Many targeted agents against angiogenesis, Ras/Raf/MAPK, EGF receptor, PI3K/AKT/mTOR, HGF/Met and IGF/IGF receptor are being tested in clinical trials.