Advanced hepatocellular carcinoma remains an entity that is hard to approach therapeutically and has shown disappointing results in terms of survival. For many years, the only accepted option for this setting was the use of a multikinase inhibitor, sorafenib. Nevertheless, through the years, a deeper knowledge has arisen about how pathogenic pathways correlate with hepatocellular carcinoma. In this review, we provide an update of the most recent data regarding new agents under investigation and new possible targets for future treatments.