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This supplement provides helpful reviews and commentaries in some of the areas where major progress has or is being made. Some of the challenges that we still face include gaining a better understanding of the replicative biology of HCV and the molecular details of viral pathogenesis, as well as the mechanisms by which the virus persists even under the pressure of powerful antivirals and is able to induce fibrosis and in the long run cirrhosis and hepatocellular carcinoma.