Hepatocellular carcinoma (HCC) is a common complication of chronic liver disease and represents the third-leading cause of death world-wide. While the majority of cases occur in Asia, the incidence has been rising in the West for some time. This is driven not only by the Hepatitis C epidemic but also the rising incidence of non-alcoholic steatohepatitis and resulting liver disease. Despite its frequency, treatments for HCC have generally been limited. Curative treatments are limited to surgical resection or liver transplant for a subset of patients and locally ablative techniques such as radiofrequency ablation (RFA) and trans-arterial chemoembolization (TACE) have been shown to extend survival for patients with unresectable and intermediate stage liver cancer. For patients with advanced HCC, sorafenib, a small molecule multitargeted kinase inhibitor is the only agent that has been shown to improve survival. At this time there is an abundance of research activity in HCC with an emphasis on developing new agents that target specific molecular alterations in HCC. In this review, we will focus on those agents currently in Phase III studies for front-line, second-line and other indications.