The current standard of care (SOC) for hepatitis C virus (HCV) genotype 1-infected patients consists of telaprevir or boceprevir in addition to pegylated interferon and ribavirin treatment. Other selective inhibitors of HCV replication are being developed. Drug pressure may, depending on the class of inhibitors, (rapidly) select for drug-resistant variants. Here we describe four different approaches to select in vitro for drug-resistant HCV subgenomic replicons.