Chronic hepatitis B virus (HBV) infection is a dynamic state of interactions among HBV, the hepatocytes and the immune system of the patient. Perinatally or early childhood-acquired chronic HBV infection has a long ‘immune tolerant phase’, when patients are young, and HBeAg seropositive with a high viral load but with no significant liver disease. Persistent or episodic liver injuries during the ‘immune clearance phase’ may lead to decompensation, fibrosis progression or cirrhosis development in some patients, but may eventually lead to HBV-DNA seroclearance with HBeAg seroconversion and entry into the ‘inactive phase’ with remission. Hepatitis may relapse, because of reactivation of HBV with precore or basal core promptor mutations, and develop ‘HBeAg-negative chronic hepatitis’, in some patients. In contrast, HBsAg seroclearance may occur in those with sustained remission. During the course, HBV replication is the key driver of disease progression including development of cirrhosis and hepatocellular carcinoma (HCC). Among the currently available anti-HBV drugs, the most extensive and longest experience has been gained with conventional interferon (IFN)-α and lamivudine. A finite course of IFN therapy has long-term benefit in achieving a cumulative response, increasing HBsAg seroclearance and reducing cirrhosis and/or HCC. Maintained virological response to lamivudine therapy has a similar long-term benefit in reducing disease progression. Pegylated IFN and newer nucleos(t)ide analogues may have even better long-term outcomes because of better therapeutic efficacy and/or a low risk of drug resistances. The treatment outcomes are still far from satisfactory. The development of safe and affordable anti-HBV agents/strategies is needed to further improve outcomes.