Recently, single-nucleotide polymorphisms near the IL28B gene have been identified as important in predicting treatment response and spontaneous clearance of the hepatitis C virus (HCV). In the less than 12 months since the initial genetic discoveries, our knowledge base has rapidly expanded regarding the significance of the IL28B polymorphism in a variety of clinical settings. For genotype 1 HCV infection, it is clear that IL28B genotype has an important role in the prediction of treatment-induced and spontaneous clearance. This association remains important in the HIV/HCV-coinfected population. Host genotype adds further discriminatory information in HCV genotype 2/3 infection. IL28B genotype may remain significant with direct-acting antiviral therapy, although further studies are needed for antiviral agents and novel immunotherapy. Information on IL28B genotype improves treatment prediction with standard of care and will integrate with existing pretreatment clinical factors and measures of on-treatment response. Pretreatment knowledge of sustained viral response may help to reshape treatment regimens of the future with the possibility of reducing therapy duration and improving tolerability, safety, and efficacy.