The hepatitis C virus (HCV) was identified as the major causative agent of post-transfusion and sporadic non-A, non-B hepatitis. Approximately 170 million individuals worldwide are afflicted with this infection that in most cases becomes persistent. The clinical outcomes are varied, ranging from an apparently healthy carrier state to liver cirrhosis and even hepatocellular carcinoma. Thus far, no vaccine is available and antiviral treatment is insufficient with only approximately 40% of patients developing a long-term sustained response. These deficits underscore the need for more effective therapies but their development has been severely hampered by the lack of an efficient cell culture system. This impediment has recently been overcome by the development of subgenomic HCV RNA molecules that replicate autonomously in transfected cells. The high level of replication of this system opens new avenues for molecular studies of various aspects of the HCV life-cycle as well as for the development of antiviral drugs.