Studies of hepatitis C virus (HCV) replication in cell culture have been greatly facilitated by the development of genetically engineered viral genomes that are capable of self-amplifying to high levels in a human hepatoma cell line. Since the original description of this 'replicon' model in 1999, important improvements have been made. Most notably, cell culture adaptive mutations were identified in various non-structural proteins that enhance RNA replication by several orders of magnitude. More recently, the permissiveness of the host cell was determined as an additional important factor contributing to efficient RNA replication. These discoveries allowed the development of transient replication assays, selectable full length genomes and a variety of novel replicons that will be useful for basic studies and facilitate the development of antiviral drugs. Ultimately, the replicon system may help to decipher the molecular basis of interferon-alpha (IFN-alpha) resistance.