The IL28B genotype is the strongest baseline predictor of hepatitis C treatment response with peginterferon-α and ribavirin. In 2011, 2 protease inhibitors were approved for genotype 1 infection in combination with peginterferon-α and ribavirin, and boceprevir and telaprevir attenuate the association between the IL28B genotype and treatment response. Although sustained virologic response rates are improved for all IL28B genotypes with the addition of the protease inhibitors, the unfavorable IL28B genotypes have substantial benefit. IL28B also predicts the likelihood of shortened duration of treatment with the protease inhibitor combination. As hepatitis C treatment moves towards interferon-free regimens, the role of IL28B in these regimens is under investigation.