Introduction: Over 70 million people are infected with hepatitis C virus (HCV), increasing the risk of cirrhosis and hepatocellular carcinoma. Areas covered: Since the approval of the first interferon-free direct-acting antiviral (DAA) therapy in 2011, a number of DAAs have been approved, and HCV is now considered curable. Until recently, however, there were no clear guidelines on how to re-treat patients who fail DAA therapy. Current protease inhibitors (PIs) are generally unaffected by earlier resistance-associated variants (RAVs), but many NS5A inhibitors continue to have overlapping resistance profiles, and NS5A RAVs can persist even in the absence of DAAs. Expert opinion: Fortunately, RAVs affecting NS5B polymerase inhibitors are rare, making sofosbuvir a safe choice as the backbone of re-treatment therapies. Recent re-treatment guidelines that take into account genotype, fibrosis, treatment history, and RAV suggest that >90% of patients with prior treatment failures can be successfully re-treated with sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir or glecaprevir/pibrentasvir.