Following the discovery of the hepatitis C virus (HCV) more than 25 years ago the field has succeeded to develop methods that have changed the safety of blood products, understand the molecular virology, epidemiology and clinical disease of HCV, and identify specific targets for the development of direct-acting antivirals for HCV cure. Nevertheless, major clinical and scientific challenges remain: therapy is still only available to a fraction of infected patients worldwide and many patients remain undiagnosed and/or live in countries where therapy is unattainable. An urgently needed HCV vaccine to eradicate infection remains still elusive. Scientifically, major questions remain regarding the life cycle, pathogenesis and mechanisms of viral clearance and persistence. Addressing these challenges, this meeting report reviews key findings of the 22nd International Symposium on Hepatitis C Virus and Related Viruses in Strasbourg, France from October 9 to 13, 2015.