Despite the successful FDA approval of sorafenib as the standard of care therapy in patients with advanced hepatocellular carcinoma (HCC), its clinical benefits have been modest. The mortality rate remains high and prognosis poor for patients with advanced-stage HCC. The exact mechanism of sorafenib in the treatment of HCC and its resistance at the molecular levels are largely unknown. There are no other treatment options in first-line therapy and there is currently no standard of care second-line therapies available. Thus, there is a critical need for novel therapeutic approaches for the treatment of advanced HCC, and thus a clear justification for the already reported, currently ongoing, and planned clinical trials.