Hepatitis C virus (HCV) infection is an emerging global health concern. Combination therapy with pegylated interferon-alpha (INF alpha) and ribavirin results in approximately 60% sustained recovery. Of the non-responders, the majority are infected with genotype 1. As a consequence, improved therapeutics are necessary to enhance response rates, especially in genotype-1-infected individuals. HCV translation is mediated by an internal ribosome entry site (IRES) located within the 5' non-translated region. Recent studies have revealed that the HCV IRES recruits the cellular translation machinery in a distinct manner compared with cellular mRNA strategies. Therefore, screening assays can be developed to identify specific inhibitors of HCV translation as a possible treatment for HCV.