The hepatitis C virus (HCV) is the main causative agent of non-A, non-B hepatitis in humans and a major cause of mortality and morbidity in the world. Currently there is no effective treatment available for the infection caused by this virus, whose replication depends on an unusual translation-initiation mechanism. The viral RNA contains an internal ribosome-entry site (IRES) that is recognized specifically by the small ribosomal subunit and by eukaryotic initiation factor 3, and these interactions allow cap (7-methyl-guanine nucleotide)-independent initiation of viral protein synthesis. In this article, we review the structure and mechanism of translation initiation of the HCV IRES, and its potential as a target for novel antivirals.