More than 50% of hepatitis C virus (HCV)-infected patients do not respond to the classical pegylated interferon (PEG-IFN)/ribavirin combination therapy. However, failing to respond to one course of treatment is not synonymous of therapy failure and retreatment is often beneficial. Alternative retreatment strategies include repeating the classical standard of care with an optimized drug regimen and adherence, including ribavirin serum concentration adjustment, correcting, if at all possible, comorbidities, and the addition of new specific anti-HCV molecules to the backbone of pegylated interferon/ribavirin. Options of retreatment should include consensus and natural interferons. For patients with advanced disease exposed to a high risk of lethal complications, customized maintenance therapy could be an effective option since it may slow down complications in some patients. Since low-dose interferon monotherapy is not sufficient, such a maintenance therapy remains to be verified via clinical trials. New possibilities of noninvasive assessment of fibrosis and the use of genetic tests to predict fibrosis progression and responsiveness to interferon are major emerging opportunities that run parallel to the revolution of the pharmacologic armentarium.