Chronic hepatitis B (CHB) remains a serious clinical problem worldwide. Advances in molecular technology have enabled the development of sensitive assays for the detection and quantification of hepatitis B virus (HBV) nucleic acid and demonstrated a positive correlation between serum HBV DNA levels and disease progression. Assessment of specific serologic and virologic factors also plays a pivotal role in the diagnosis and effective management of individuals with CHB. Recent development of quantitative assays for intrahepatic HBV replicative intermediates, as well as hepatitis B e antigen and hepatitis B surface antigen, has spurred investigation into the relationship between these factors and response to antiviral therapy and disease progression. Recent findings from preclinical and clinical investigations indicate that these factors may have promise in identifying patients likely to respond to treatment. Additional work is needed to standardize and validate these assays before they can be considered to be of true diagnostic value. Further evaluation is needed to decide which will have the greatest clinical applicability.