Advances in our understanding of the hepatitis C virus (HCV) life cycle have enabled the development of numerous clinically advanced direct-acting antivirals. Indeed, the recent approval of first-generation direct-acting antivirals that target the viral NS3–4A protease and NS5B RNA-dependent RNA polymerase brings closer the possibility of universally efficacious and well-tolerated antiviral therapies for this insidious infection. However, the complexities of comorbidities, unforeseen side effects or drug–drug interactions, viral diversity, the high mutation rate of HCV RNA replication and the elegant and constantly evolving mechanisms employed by HCV to evade host and therapeutically implemented antiviral strategies remain as significant obstacles to this goal. Here, we review advances in our understanding of the HCV life cycle and associated opportunities for antiviral therapy. ; Nicholas S Eyre, Karla J Helbig and Michael R Beard ; Review