Hepatitis C virus (HCV), the primary etiologic agent of parenterally transmitted non-A, non-B hepatitis, is a major cause of acute and chronic hepatitis and cirrhosis worldwide. The most efficient transmission of HCV is associated with percutaneous exposures to blood, but such exposures account for less than half of reported cases. Sexual, household, and perinatal transmission also seem to occur, but the risks associated with these types of exposures are still unknown. Virtually all persons with acute HCV infection seem to become chronically infected, and chronic liver disease with persistently elevated liver enzymes develops in an average of 67%, independent of the source for infection. The extraordinarily high rate of persistent infection observed in humans and the lack of protection against rechallenge with homologous HCV strains demonstrated in experimental studies in chimpanzees suggest that HCV fails to induce an effective neutralizing antibody response. This raises major concerns for the development of effective passive or active immunization against hepatitis C, and prevention may depend on a better understanding of the factors that facilitate the transmission of HCV infection.