In spite of existing vaccines, methods for infection prevention, and an increasing number of antiviral drugs chronic HBV infections remain a major healthcare problem. Chronic HBV infections lead to severe late consequences in the majority of cases like liver cirrhosis and hepatocellular carcinoma. Consequently a large number of those infections are in need for treatment in order to avoid these late features of the chronic infection and to prevent a worsening of the clinical course. Unfortunately, with the use of antiviral drugs resistant viral strain emerge; moreover, in the special case of chronic HBV infection and even worse in co-infections with HIV, host mechanisms seems to influence the outcome of the antiviral therapy and to contribute to a kind of host resistance. This article hypothesizes the putative reasons for such host resistance that should become a focus in the systematic search for causes of therapy failures with the aim to optimize the antiviral therapy and to reduce the emergence of resistance.