HCV infection becomes persistent in many patients who are otherwise immune competent. There is increasing support for potential contribution of innate immune response and viral interference with its components to the subsequent outcome. As for the adaptive immune response, humoral immunity may be largely ineffective despite evidence for neutralizing antibody response directed to the E2 HVR region, perhaps due to rapid selection of antibody escape variants. Cellular immune response does seem to play a role in the virologic outcome during acute infection based on strong association of a sustained vigorous and multispecific antiviral CD4 and CD8 T cell response with HCV clearance during acute infection. Following clearance, vigorous CD4 T cell response to HCV is maintained for many years, whereas the memory CD8 T cell response may be maintained with variable efficiency. If unable to clear the virus quickly, the T cell response (particularly if focused) may also select for T cell escape variants that are poorly recognized by the circulating T cells or even actively inactivate them through T cell antagonism. In established chronic infection. HCV-specific T cell response is quantitatively weak, providing only minimal selection pressure for further escape mutation. Although earlier studies using conventional in vitro techniques suggest that this low-frequency T cell response may help control the virus and liver disease progression, the role and nature of these apparently defective T cells in the outcome of chronic HCV infection remains to be fully determined. In summary, much progress has been made in the field of HCV immune pathogenesis since the initial identification of HCV. Although more work is needed to define the mechanism of HCV persistence and liver cell injury, there is considerable hope as well as challenge for potential development of vaccine and immunotherapy for HCV infection (see article by Drs. Inchaupsé and Feinstone). A better understanding of the relevant host and viral factors for clinical and virologic outcome, and the mechanism of selective immune defect against HCV, will be invaluable in our ability to treat the many patients infected with HCV.