The current epidemic of HCV infection affects almost 180 million people, of whom one quarter already has cirrhosis. The number with hepatocellular carcinoma and liver failure are projected to treble over the next three decades. The only means of reducing this health burden is through increased eradication with antiviral therapy. However, current antiviral therapies are limited by poor efficacy and tolerability, especially in patients with HCV genotype 1. Pegylated interferon (PEG-IFN) plus ribavirin (RBV) has significant side effects, must be administered for up to 48 weeks and cures about less than half of patients. Many patients diagnosed with chronic hepatitis C are unsuitable for or refuse to undertake such therapy. Although the recent approval of triple therapy with telaprevir or boceprevir with PEG-IFN/RBV has increased cure and reduced duration of therapy, this is still unsuitable for patients either intolerant of or with contraindications to IFN or RBV. In addition, triple therapy will have limited benefit in previous null responders to PEG-IFN/RBV, and in those with advanced fibrosis. Finally, few protease inhibitors have antiviral efficacy in patients infected with non-1 genotype HCV. Thus, there is an urgent need for the development of an IFN-free, all-oral treatment regimen consisting of direct-acting antiviral drugs with different mechanisms of stopping the virus and a higher barrier to resistance, which can improve cure rates across all HCV genotypes. The likely successful regimen will contain at least two direct-acting antivirals with different targets of action, of which at least one will have a high barrier to resistance. The likely duration of IFN-free direct-acting antiviral therapy will be between 6 and 12 weeks depending on early-on-treatment virological responses.