Chronic infection with hepatitis C virus (HCV) is a major global health problem; there are approximately 120 to 130 million chronic infections worldwide. Since the discovery of HCV 24 years ago, there has been a relentless effort to develop successful antiviral therapies. Studies of interferon-α-based therapies have helped define treatment parameters, and these treatment strategies have cured a substantial percentage of patients. However, interferon-α must be injected; there are problems with tolerability, adherence, and incomplete response in a large percentage of patients. New drug candidates designed to target the virus or the host have recently been introduced at an unprecedented pace. In phase I-III studies, these agents have exceeded expectations and achieved rates of response previously not thought possible. We are, therefore, entering a new era of therapy for HCV infection and interferon independence.