Non-responders to hepatitis C virus (HCV) antiviral therapy comprise a very heterogeneous population for whom the optimal management strategy remains to be determined. Liver damage in these patients may progress to cirrhosis, and they are at risk of developing hepatocellular carcinoma. Non-responders to interferon monotherapy and relapsers to interferon plus ribavirin could benefit from re-treatment, even for 48 weeks, with pegylated interferon plus ribavirin. Regarding patients who failed pegylated interferon plus ribavirin, whether there is benefit in re-treatment is still up for debate. Probably, those patients who had poor compliance, or who presented with advanced fibrosis in liver biopsy, or who experienced treatment discontinuation due to a severe cytopenia could benefit from another cycle of treatment, in the majority of cases, with an extended duration of pegylated interferon plus ribavirin. On the other hand, maintenance therapy continues to draw controversy. In the future, novel approaches such as therapeutic vaccines and immunomodulatory drugs, including ones targeting intracellular cytokine pathways, must be explored.