Unresectable or metastatic hepatocellular carcinoma (HCC) carries a poor prognosis. Hepatic reserve often dictates the therapeutic options. There have been multitudes of negative systemic therapy trials for advanced HCC unsuitable for surgical and locoregional therapy up until now. Hormonal drugs, such as tamoxifen or immune response modifiers such as interferon and thalidomide are mostly ineffective. Recently, long-acting octreotide has shown to improve the survival and quality of life in somatostatin receptors positive patients with advanced HCC. It should be verified in well designed controlled trials. In general, efficacy of conventional cytotoxic chemotherapy is poor. Growth factors and their corresponding receptors are commonly overexpressed or dysregulated in many cancers. There is a strong rationale for the drug inhibition of molecular components of proliferative and angiogenic components of signaling pathways in HCC, a hypervascularized neoplasm. Recently, in a randomized, placebo controlled trial, sorafenib, an oral multikinase inhibitor (Tab Nexavar® 200mg, in a dose 400 bid), has been found safe and effective for the first time in prolonging survival of patients with advanced HCC and preserved liver function (compensated cirrhosis). This effect is clinically meaningful and established sorafenib as first-line treatment for these patients. After this landmark study, several molecularly targeted therapies, alone or combined with chemotherapy or locoregional attempts, are currently under evaluation for advanced HCC. Nevertheless, the side effect profile of each regimen must be carefully considered in patients with advanced liver disease.