The current standard of care for the treatment of hepatitis C virus infection, pegylated interferon-alpha and ribavirin, is costly, associated with significant side effects, and effective in only 50% of patients. There is therefore a need for the development of novel antiviral therapies. One such approach involves the application of gene silencing technologies, including antisense oligonucleotides, ribozymes, RNA interference, and aptamers. However, despite great scientific advances over the past decade, and promising in vitro data, several significant challenges continue to limit the translation of this technology to the clinical setting. This review provides a concise update of the current literature.