New insights into the early viral evolution and cellular immune response during acute hepatitis C virus (HCV) infection are being gained following a global outbreak in human immunodeficiency virus-1 (HIV)-positive men who have sex with men. Cross-sectional and longitudinal sequence analysis at both the population and individual level have facilitated tracking of the HCV epidemic across the world and enabled the development of tests of viral diversity in individual patients in order to predict spontaneous clearance of HCV and response to treatment. Immunological studies in HIV-positive cohorts have highlighted the role of the CD4+ T-cell response in the control of early HCV infection and will increase the opportunity for the identification of protective epitopes that could be used in future vaccine development.