Several approaches have been undertaken in the attempt to inhibit hepatitis C virus (HCV) translation. Antisense oligonucleotides (AS ONs) have proven to be invaluable in the characterization of the HCV internal ribosome entry site (IRES). Chemical modification of oligonucleotides has resulted in optimized stability and specificity. Artificial ribozymes have also been developed to target the HCV IRES. Both techniques have demonstrated efficacy in vitro and in vivo. Various studies have identified cellular cofactor proteins that are required for IRES function, which may present themselves as intervention targets. Recent experiments have revealed that the HCV IRES uses a novel mechanism of recruiting translational components. These new advances in understanding the mechanism of HCV translation could lead to the development of novel IRES inhibitor strategies.