Chronic hepatitis B virus (HBV) infection is a dynamic series of interactions between HBV, hepatocytes and the patient's immune system. HBV replication is the key motor of disease progression, including the development of cirrhosis and hepatocellular carcinoma (HCC). HBV elimination or suppression can reduce the risk of or slow the progression of liver disease. Studies have shown that a finite course of conventional interferon-α (IFN) therapy provides long-term benefit for achieving a cumulative response as well as reducing the progression of fibrosis and the development of cirrhosis and/or HCC. Long-term therapy with nucleos(t)ide analogues (NUCs) may also improve fibrosis or reverse advanced fibrosis as well as reduce disease progression and the development of HCC. The problems associated with drug resistance can be overcome by the timely use of rescue NUCs without cross-resistance. The outcome with pegylated IFN (PEG-IFN) and newer NUCs may be even better because of more effective treatment and/or a low risk of resistance. However, the treatment outcomes still need to be improved, and more effective, safe and affordable anti-HBV agents/strategies are needed.