The tolerogenicity of the liver renders it vulnerable to hepatotrophic pathogens such as hepatitis B virus (HBV) and hepatitis C virus (HCV). Both viruses have successfully co-evolved within the human host by evading and counteracting immune control. Inadequate cell culture and animal models have limited definitive characterization of the immunological mechanisms arbitrating virus and host co-existence. The clinical sequelae of chronic viral hepatitis such as cirrhosis and hepatocellular carcinoma are not directly mediated by the viruses but rather by hepatotoxic immunological mediators and cytokines. The pro-fibrotic T helper 2 (Th2) response promoted by this altered cytokine milieu is associated with viral persistence. In this chapter, the innate and adaptive immune response to acute and chronic HBV and HCV is reviewed with particular focus on its clinical implications.