Hepatitis C virus (HCV) infection is the most common chronic bloodborne infection in the United States, and most infected persons are younger than 50 years old. The relative importance of the two most common exposures associated with transmission of HCV, blood transfusion and intravenous drug use (IVDU), has changed over time. Blood transfusion, which accounted for a substantial proportion of HCV infections acquired >10 years ago, rarely accounts for recently acquired infections. In contrast, IVDU has consistently accounted for a substantial proportion of HCV infections and currently accounts for 60% of HCV transmission while sexual exposures account for up to 20%. Other known exposures (occupational, hemodialysis, household, perinatal) together account for about 10% of infections. In the remaining 10%, no recognized source of infection can be identified, although most persons in this category are associated with low socioeconomic level. Case-control studies have found no association with military service or exposures resulting from medical, surgical or dental procedures, tattooing, acupuncture, ear piercing or foreign travel. Reducing the burden of HCV infection and disease in the United States requires implementation of primary prevention activities that reduce or eliminate HCV transmission and secondary prevention activities that reduce liver and other chronic diseases in HCV-infected persons by identifying them and providing appropriate medical management and antiviral therapy. Surveillance and evaluation activities also are important to determine the effectiveness of these programs in reducing the incidence of disease, identifying persons infected with HCV, and promoting healthy lifestyles and behaviors.