Chronic hepatitis C (HCV) infection is a systemic life-threatening condition that can lead to hepatic and extra-hepatic complications. Sustained virological response (SVR) is associated with a regression of most liver and non-liver manifestations, which reduce mortality. The history of HCV infection therapy radically changed in the last decade, with the introduction of the first generation direct acting antivirals (DAAs). Areas covered: The new regimens, based on the combination of 2 or 3 second-generation DAAs, allow SVR, namely hepatitis C infection cure, in more than 95% of cases. Antiviral treatment is generally well tolerated and its duration (8-16 weeks) varies depending on the stage of liver fibrosis, HCV genotype, prior treatment, baseline viral load, presence of resistance-associated variants (RAV). This review evaluates the cause, the efficacy and safety results in case of DAAs failure. Expert commentary: Despite the excellent efficacy of DAAs, a minority of patients (4-5%) still fail to eradicate HCV, mainly related to poor adherence but also to relapse or viral breakthrough. The main causes of a failure of DAAs are the presence of advanced liver disease, suboptimal treatment and NS5A mutations. Many questions regarding resistant associated substitutions (RASs) prevalence and clinical relevance in re-treatment remain unanswered.