Increased treatment options that are more efficacious and safe and new knowledge on the natural history of chronic hepatitis B virus (HBV) infection have expanded the indications for therapy in hepatitis B. The question is no longer "Who should be treated?" but "When should treatment be initiated?" Treatment is clearly indicated in patients with life-threatening liver disease (acute liver failure, decompensated cirrhosis, or severe hepatitis flare) and in those with compensated cirrhosis and high levels of serum HBV DNA. For patients with precirrhotic liver disease, treatment indications should be based on clinical, biochemical, or histological evidence of liver disease, such as elevated alanine aminotransferase (ALT) levels, abnormal histology, and high levels of serum HBV DNA. The cutoff for ALT and HBV DNA values are constantly being revised and should be set at a lower level for older patients who may have been infected for a longer period of time. High serum HBV DNA levels persisting for a few decades are associated with increased risk of clinical outcomes, but there is insufficient data to support the initiation of treatment based on high serum HBV DNA alone, particularly in young patients, those with persistently normal ALT levels, and those with a single high HBV DNA level. The decision to initiate treatment at the time of assessment or to defer treatment should take into consideration other factors such as desire to start a family, occupational requirement, family history of hepatocellular carcinoma, access to care and insurance coverage, and commitment to long-term treatment and medication compliance. All patients who are not initiated on treatment should continue to be monitored so treatment can be started if and when the indication arises. (HEPATOLOGY 2009;49:S129-S137.