Therapies for hepatitis B virus (HBV) have continued to evolve, and new therapies for hepatitis C virus (HCV) will soon be available in clinical practice. These medications for hepatitis C will mark the first time that direct antivirals that target HCV functions have been used. When such drugs are used as single agents, previously existing mutants with reduced susceptibility to them are rapidly selected. The relationship between these drug-resistant mutants and "wild-type" virus is unclear, but resistant strains likely have the potential to maintain the progression of liver disease despite successful treatment of "wild-type" virus. Resistant HBV and now HCV are already a clinical problem. The same issue was recognized very early in the development of therapy against HIV, with azidothymidine-resistant mutants detected within the first weeks of therapy. Clinical investigation and a progressive understanding of the pathogenesis of the disease overcame this challenge and led to the substantial and durable benefits of antiretroviral therapy that are evident today. To bring experts from the fields of HIV and viral hepatitis virology and therapy together for interactive discussions about how to apply the lessons from HIV to the further development of viral hepatitis therapy, the American Association for the Study of Liver Diseases held a single-topic conference entitled "Viral Hepatitis Therapy: Lessons to be Learned From HIV" on 24-26 July 2008. This article summarizes that conference.Am J Gastroenterol advance online publication, 19 January 2010; doi:10.1038/ajg.2009.726.