Therapy for chronic hepatitis C has improved dramatically over the past 20 years. Unfortunately, approximately 50% of those treated do not have a durable response to therapy. Non-responders and relapsers after previous interferon-based therapy are particularly challenging with regard to clinical management. This article provides a general overview of the treatment of hepatitis C and reviews present data regarding management of patients with chronic hepatitis C who are non-responders or relapsers after previous treatment. The review ends with the authors' opinion regarding present management of non-responders and relapsers and future emerging therapies.