Because clearance of hepatitis B virus (HBV) infection is rarely, if ever, achievable, the goals of therapy necessarily focus on prevention of bad clinical outcomes. Ideally, therapies would be shown to prevent tangible clinical endpoints like development of cirrhosis, end-stage liver disease and hepatocellular carcinoma. However, these endpoints typically take years or decades to occur and are therefore impractical targets for clinical trials which last only 1-2 years. As a result, surrogate biomarkers that are believed to correlate with long-term outcome are used to evaluate therapy. Of the clinical, biochemical, serological, virological, and histological endpoints that have been evaluated, none has been shown to be ideal on its own. Symptoms are uncommon and aminotransferase levels fluctuate spontaneously. Loss of hepatitis B e antigen (HBeAg) has been the traditional therapeutic endpoint; however, the indefinite durability off treatment and the emergence of HBeAg-negative disease have made it inadequate as the sole goal of therapy. Loss of hepatitis B surface antigen is associated with improved clinical outcomes, but it is rarely achieved with current therapies. Suppression of viral replication, as measured by serum HBV DNA levels, has become the major goal of therapy, particularly if maintained off therapy. Although useful, the significance of viral levels depends on the stage of disease, degree of liver damage, and the type of therapy. Finally, liver biopsy, often considered the gold standard, is invasive, prone to sampling error, and may take years to change significantly.At present, there is no ideal biomarker for evaluation of therapies for hepatitis B. Future research should be directed at development and validation of surrogate markers that accurately predict or reflect clinically relevant outcomes of chronic hepatitis B. (HEPATOLOGY 2009;49:S96–S102.)