Treatment of hepatocellular carcinoma has dramatically changed in the last years. The better knowledge of the molecular mechanisms responsible of tumor initiation and progression has allowed the development of molecular targeted therapies that specifically block the disrupted pathways. Among all these new agents, Sorafenib is the only one that has shown efficacy in terms of survival in advanced stage in two randomized, double-blind, controlled trials. The positive result of these two trials are the proof of the efficacy of molecular targeted therapies in hepatocellular carcinoma and opens the door to multipathway blockade and the use of these targeted therapies in the adjuvant setting. Other agents have shown promising results in phase 1-2 trials but further studies are needed to demonstrate their efficacy. In the next years, efforts should be directed to identifying genomic and proteomic profiling that will help us to assess the prognosis and to define what treatment benefits whom, ultimately giving way to personalized medicine.