Abstract: RNA interference (RNAi) is the process of sequence-specific gene silencing, initiated by double-stranded RNA that is homologous in sequence to the target gene. This unique phenomenon has been extensively investigated during the last few years not only in the context of its mechanism and its possible role in the regulation of gene expression and cell function, but also as a potential powerful tool for gene therapy. Targeting essential viral genes or oncogenic alleles are only some of the possible applications of RNAi in the field of gene-directed therapy. This review covers the potential use of RNAi against hepatitis B and hepatitis C viruses, the main pathogens causing chronic liver disease. The major milestones along the discovery of RNAi will also be covered.