The management of chronic hepatitis B virus (HBV) infection requires understanding the natural history of the disease as well as the risks, benefits, and limitations of the therapeutic options. This article covers the principles governing when to start antiviral therapy, discusses recent advances using hepatitis B surface antigen quantification to better define various phases of infection, describes the use of HBV core, precore, and viral genotyping as well as host IL28B genotyping to predict response to interferon therapy, and reports on the management of HBV in 3 special populations (pregnancy, postliver transplantation, and in the setting of chemotherapy or immunosuppression).