S Chinnaswamy, H Cai, C KaoDepartment of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, USAAbstract: Chronic infection by the hepatitis C virus (HCV) can lead to liver cirrhosis and hepatocellular carcinoma. There is currently no prophylactic vaccine against HCV, and the treatment is currently limited to modified interferon and ribavirin. The RNA-dependent RNA polymerase (RdRp) of HCV is an attractive target for inhibitor development, and this has led to active efforts in the development of nucleoside and non-nucleoside inhibitors. The HCV polymerase is also one of the model systems for detailed analysis of how RdRp structure affects the mechanism of RNA synthesis. This review summarizes current efforts with inhibitors targeting the HCV RdRp and how the various inhibitors affect the mechanism of RNA synthesis.Keywords: HCV infection, RdRp, nucleoside inhibitors, subgenomic replicons, ProTides, ribavirin, allosteric site