Hepatitis C virus (HCV) infection remains a global health problem. Unfortunately there is no preventive vaccine for HCV infection. The common standard treatment for HCV is pegylated interferon α (PEG-IFNα) plus ribavirin, which is non-specific and has strong side effects. Recently, the combination with the HCV protease inhibitor has been approved to improve the sustained virologic response although still far away from cure. Therefore, we are still on the way of developing more effective and specific antiviral treatments with diverse mechanisms of action against HCV. Viral replication is a key and complicated step during HCV life cycle. Besides those specific HCV viral proteins that are involved in the replication, host cellular factors that are key to control efficient viral replication and promote host immune response against HCV could also be the targets for novel antiviral treatments. This review focuses on these aspects and summarizes some recent progress on the related three aspects.