Complications from chronic hepatitis C (HCV) and recurrent HCV post-transplant are responsible for significant morbidity and mortality in the United States and Europe. Current antiviral therapies are at best, effective in up to 50% of patients in the pre-transplant setting, and in the post-transplant setting are associated with more limited efficacy and increased toxicity. With this reduced efficacy of antiviral strategies in the post-transplant setting, new approaches are urgently needed. Substantial progress has been made in understanding the pathogenesis of hepatic fibrosis over the last 20 years, which has yielded potential new therapeutic targets. The prospect of antifibrotic therapies is nearing reality in order to reduce progression to cirrhosis, thereby reducing morbidity, mortality and the need for re-transplantation. Current and evolving approaches primarily target the activated hepatic stellate cells, which are the main source of extracellular matrix, along with related fibrogenic cell types. Key issues yet to be clarified include the optimal duration of antifibrotic therapies, endpoints of clinical trials, indications in clinical practice and whether combination therapies might yield synergistic activity.