With the approval in 2011 of the protease inhibitors Victrelis and Incivek, direct-acting antivirals have begun to revolutionize HCV treatment. Although the addition of Incivek or Victrelis to PEGylated IFNα and ribavarin (pIFNα/RBV) may improve cure rates and shorten the treatment duration of the "old" standard of care (SOC), this triple therapy will not be suitable for patients intolerant to pIFNα or RBV. The efficacy of this triple therapy will also certainly be attenuated in pIFNα/RBV non-responders. As Incivek is inactive against genotype 3 (GT3) combined with the fact that all protease inhibitors and most of the non-nucleoside polymerase inhibitors in development are active primarily against GT1, pIFNα/RBV will remain the SOC for non-GT1 until new classes of inhibitors enter into clinical practice. GT1 patients who do not respond to this new triple therapy will have developed resistance to protease inhibitors that will limit future treatment options. There is thus an important need for the identification of new potent HCV agents. A novel class of HCV inhibitors that have great potential for the treatment for HCV has recently emerged: the host-targeting antivirals cyclophilin inhibitors.