New treatment options for HCV infection with Direct-Acting Antivirals (DAAs) increased SVR rate in treated patients but on the other hand drew attention to the problem of HCV drug resistance. Drug-resistant HCV mutants are present in all infected patients even before the treatment initiation and their number grows significantly over the first few days of DAAs therapy. But HCV has no known genetic form of intra-cellular persistence (does not integrate with host's genome and cannot produce episomal forms) which enables its total eradication. It is likely that the effective interferon-free, based on all-oral DAAs drug combination will be available within the next few years. This paper reviews HCV resistance mechanisms and their significance in treatment. I also presents results of recent DAAs trials.