Four landmark studies in 2009 described a clinical association between IL28B genotype and hepatitis C virus (HCV) genotype 1 outcomes to pegylated interferon and ribavirin combination therapy. These studies were novel in the HCV field because, for the first time, genome-wide association, instead of a candidate gene approach, was utilized. Since then, extensive efforts have investigated the link between IL28B and many other aspects of HCV infection. It is now apparent that IL28B polymorphisms not only impact HCV genotype 1, but also genotype 2 and 3 outcomes, spontaneous recovery from HCV infection, as well as posttransplant HCV reinfection and subsequent treatment response. Population studies have demonstrated significant differences in the allelic frequencies of single nucleotide polymorphisms in the IL28B gene, clarifying to some degree, previously noted geographic and ethnic differences in treatment response. This review summarizes the current understanding of the role of the IL28B gene in HCV infection, its clinical impact, and the potential for future drug development.