The majority of acute HCV infections progress to chronicity, implying that the immune response is unable to clear virus in most instances. Reinfection with a second strain of HCV after clearance of an initial infection has been reported in several recent studies. Moreover, individuals with HCV infection may be at risk of HCV superinfection with a second strain of HCV even after the establishment of persistent infection and the development of an immunological response to the initial virus. In vivo and in vitro data regarding HCV reinfection and superinfection, including the clinical consequences of these phenomena and the impact they have on vaccines require consideration in future studies.