Hepatitis C virus (HCV) is a leading cause of chronic viral hepatitis affecting 130-150 million people world-wide. HCV is an RNA virus of the Flaviviridae family, containing ~9600 nucleic acids coding for structural and nonstructural proteins, divided into 7 genotypes of which the most prevalent is genotype 1. The goal of HCV therapy is to achieve sustained virological response (SVR), currently defined as undetectable serum HCV RNA 12 weeks post-treatment. Treatment with the new direct acting antivirals (DAAs) that target the HCV protease NS3/4A, NS5A and the NS5B polymerase proteins can lead to more than 90% SVR. Successful treatment depends, among other factors, on the viral genotype and subtype and the barrier to resistance which depends on the number of mutations needed to cause drug resistance. To ensure effective treatment the HCV subtype should be determined prior to therapy. Resistance mutations that affect the new DAAs and are located in the three HCV drug target proteins have already been defined. The relevance of resistance testing in DAAs naïve individuals is controversial, though current American Association for the Study of Liver Diseases (AASLD) guidelines do recommend testing for Q80K mutation in the NS3 protein prior to simeprevir therapy and for the L31V/A and Y93H/N mutations in the NS5A prior to daclatasvir therapy. In cases of DAAs treatment failure, though the European Association for the Study of the Liver (EASL) guidance is not conclusive, the new AASLD guidance recommends NS3/4A and NS5A resistance testing prior to retreatment. Collecting more data on the frequency of resistance mutations prior to DAAs therapy and following virological failure will assist in future retreatment planning and potential eradication of HCV.