The exponential increase in the number of publications related to hepatitis C antiviral research both from academia and the pharmaceutical industry in recent years highlights the intense interest in combating this pathogen. The number of: people infected with hepatitis C virus (HCV) (4 million in the US, nearly 200 million worldwide), as well as the poor tolerability and disappointing efficacy of IFN-based treatments make obvious the need for improved therapeutic options. Promising advances have been made, including the advent of improved IFN-based treatments as well as a small number of early clinical trials of novel therapies. Perhaps the most positive development has been the disclosure of what may finally be a reproducible, logistically feasible cell-bused HCV RNA replication and expression system. It continues to remain highly likely, however, that a number of potent and specific drugs against HCV will ultimately be required in order to effectively combat HCV infection.