Advanced hepatocellular carcinoma (HCC) is a deadly disease with few systemic therapeutic options. Sorafenib is the only agent to be FDA approved for the first-line treatment of patients with HCC. This drug increases overall survival (OS) by 3 months compared with placebo (10.7 months with sorafenib . 7.7 months with placebo). More recently, the RESORCE trial demonstrated efficacy of regorafenib in the second-line treatment of HCC: OS was increased from 7.8 months with placebo to 10.6 months with regorafenib after patients experienced disease progression on sorafenib. However, there is still an unmet need for effective systemic therapy of patients with advanced HCC. Numerous genetic pathways have been studied along with drugs to target these pathways but, thus far, drugs targeting cell proliferation, metastasis, angiogenesis, and metabolite use have been studied with minimal success. HCC can be divided into two subclasses: proliferative and non-proliferative, each dependent on separate pathways. HCC can be caused by alcoholic cirrhosis, hepatitis C virus (HCV), and hepatitis B virus (HBV); however no etiology-specific therapies have been demonstrated. Immunotherapy is currently being assessed in clinical trials and is demonstrating some efficacy. More research is needed to determine the most essential pathways to target in the war against this deadly cancer.