Hepatitis C virus (HCV) is one of the most successful human pathogens. Most of acute HCV infections are rapidly developed to chronic infections, which leads to liver cirrhosis and ultimately to hepatocellular carcinoma (HCC). A protective vaccine is not yet available, and current therapeutic options can only result in sustained virus clearance in a small population. MicroRNAs (miRNAs) are small non-coding RNAs functioning as negative regulators of host gene expression. Until now, microRNA-122 (miR-122) and its application in HCV infection have been the focus of different published studies, leading to studying HCV infection and to identifying new therapeutic targets. This review will highlight the impacts of miR-122 on HCV replication and the possible miRNA targets for therapy of chronic hepatitis.