Treatment of advanced hepatocellular carcinoma remains a challenge, with discouraging results in terms of survival. Following the approval of the multikinase inhibitor sorafenib, a large number of molecular targeted agents have been tested, but many have failed to demonstrate significant efficacy in clinical trials. However, the deeper knowledge in HCC pathogenesis achieved through the years has enabled us to explore new targetable pathways as well as biomarkers that could lead to treatment personalization. In this review, we provide a comprehensive update of the most recent data regarding new drugs under investigation ‒ some like regorafenib, very close to its approval ‒ and new possible targets for future treatments.