Identified in 1989 as the cause of what was then known as hepatitis non-A non-B, the hepatitis C virus (HCV) continues to be a significant global public health threat, given that an estimated 123 million individuals are chronically infected and, thus, at risk for cirrhosis and hepatocellular carcinoma. After 20 years of basic and clinical research into HCV infection, the backbone of therapy has remained interferon, a drug that - in a different formulation - was already being employed before HCV was even identified. Nonetheless, research has overcome many obstacles that stood in the way of studying this pre-eminent human pathogen. Hard-won insights into its molecular biology have identified promising therapeutic targets, and we are now on the verge of an era where rationally designed therapeutics, also referred to as specifically targeted antiviral therapy for HCV, will reshape the treatment of hepatitis C. This article describes recent insights on the molecular biology of HCV and the efforts to translate them into clinical applications.