Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most lethal neoplasm, causing an estimated 700000 deaths annually. Currently HCC has only one systemic molecular targeted therapy, the multi-kinase inhibitor, sorafenib. The standard-of-care for advanced liver cancer is limited because sorafenib can expand the median life expectancy of patients for only 1 year. Thus there is an urgent need to develop a novel molecular targeted therapy to improve therapeutic outcomes for HCC. HCCs are phenotypically and genetically heterogeneous tumors driven by diverse molecular mechanisms. However, HCCs exhibit certain common traits selected through genetic and epigenetic alterations. The identification of common molecular alterations may provide an opportunity to develop more effective anticancer treatment through targeted therapy. Recent studies in liver cancer biology have revealed a limited number of molecular targets responsible for initiating and maintaining dysregulated cell proliferation, including vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), c-mesenchymal-epithelial transition factor-1 (c-Met), mammalian target of rapamycin (mTOR) and histone deacetylases (HDACs). New treatments involving inhibitors targeting several of these critical pathways are in development. This review describes the current understanding of target pathways, ongoing clinical trials using HCC-targeted agents, and future directions in the treatment of HCC.