Hepatitis C virus is one of the major causative pathogens of chronic hepatitis and the second most common cause of hepatocellular cancer. The virally encoded NS5B RNA-dependent RNA polymerase is a vital component of the replicase complex that orchestrates the replication process leading to the production of progeny virus. In recent years, developing novel drugs to target NS5B polymerase has become one of the important strategies for the treatment of chronic hepatitis C infection. This review highlights the structure and scaffold of the non-nucleoside NS5B inhibitors represented in the past five years.