In two randomized controlled trials (Sorafenib HCC Assessment Randomized Protocol trial and Asian Pacific trial), sorafenib has demonstrated a significantly favorable disease control rate, progression-free survival and overall survival in advanced hepatocellular carcinoma in comparison with placebo. It is presently acknowledged as a standard treatment for advanced hepatocellular carcinoma and is available worldwide. However, the survival benefit and toxicity of sorafenib have been in sufficient, so development of new agents has been more active recently. Development treatment of hepatocellular carcinoma revolves around molecular targeted drugs that target factors associated with tumor growth and angiogenesis. In Japan, clinical trials have involved cytotoxic therapies, but the development of systemic agents for advanced hepatocellular carcinoma has been lacking despite no clear benefits from traditional cytotoxic therapies. S-1, an oral fluoropyrimidine, is currently under evaluation for the treatment of hepatocellular carcinoma in randomized controlled trials. Systemic chemotherapy for hepatocellular carcinoma has been greatly advancing, and further improvements of chemotherapy in hepatocellular carcinoma are expected.