RNA interference (RNAi) is a sequence-specific post-transcriptional gene silencing by double-stranded RNA. Because the phenomenon is conserved and ubiquitous in mammalian cells, RNAi has considerable therapeutic potential for human pathogenic gene products. Recent studies have demonstrated the clinical potential of logically designed small interfering RNA (siRNA). However, there are still obstacles in using RNAi as an antiviral therapy, particularly for hepatitis C virus (HCV) that displays a high rate of mutation. Furthermore, delivery is also an important obstacle for siRNA based gene therapy. This paper presents the potential applications and the hurdles facing anti-HCV siRNA drugs. The present review provides insight into the feasible therapeutic strategies of siRNA technology, and its potential for silencing genes associated with HCV disease.