An association between variations at the IL28B gene locus and HCV clearance (spontaneous recovery or sustained virological response under pegylated interferon (PEG-IFN) and ribavirin (RBV) has been extensively described. In genotype 1-infected patients, the new direct antiviral agents (DAA) including the two approved protease inhibitors boceprevir and telaprevir, in association with the PEG-IFN/RBV combination is the new standard of care making it necessary to redefine the interest of the IL28B genotype in the decision to treat and how to treat genotype 1-infected patients. In treatment-naïve patients, IL28B status can certainly identify those with a high probability of achieving SVR with response guided therapy and probably in whom the duration of treatment can be markedly reduced. In experienced patients, the impact of IL28B genotypes is limited and cancelled by early viral kinetics. However, the decision to initiate or withhold therapy remains a clinical one. In summary, although it was a major milestone in the treatment of patients with PEG-IFN/RBV,IL28B polymorphism testing entered the clinical arena almost 10 years too late.