Hepatocellular carcinoma cell lines supporting HCV replication in culture produce infectious particles (cell culture-derived HCV) for only a limited number of strains. Mutations in the viral genome resulting from the combined effects of the error-prone HCV RNA polymerase coupled with selection of the best-adapted viral variants generate a drift in cell culture-derived HCV properties, which can result in a total loss of in vivo infectivity in the chimpanzee model. Other systems for producing HCV or HCV-related particles, some of which bypass HCV RNA replication, have been developed to study the biology of this virus, with limitations of their own. This review briefly analyzes the pros and cons of these in vitro models, focusing on recent advances.