Chronic infection with hepatitis B virus (HBV) is a major global health problem and an important cause of morbidity and mortality from sequelae of liver cirrhosis and hepatocellular carcinoma. In the past decades, better understanding of the natural history and immunopathogenesis of chronic HBV infection and of the development of many powerful antiviral agents has allowed us to improve therapeutic efficacy. Among these agents, nucleos(t)ide analogs are important and potent viral suppressors. However, when administered alone, they are not able to permanently eradicate HBV, and long-term maintenance therapy is required for therapeutic efficacy. Additionally, prolonged treatment is frequently associated with the emergence of drug-resistant HBV mutants. Before an 'ideal' drug(s), or drug combination, with optimal antiviral efficacy and negligible rates of drug resistance becomes available, the on-treatment monitoring approach using serum HBV DNA level as a predictor for therapeutic efficacy and drug resistance is useful. However, most countries in the Asia-Pacific region have low income economies, insufficient medical care systems, and low awareness of the disease among the general population and government officers. The easy approach of the road-map concept using an affordable drug to treat chronic HBV infection is more important in this region. There is already evidence that the long-term outcomes of chronic HBV infection can be improved under well-managed antiviral therapy. Profound and long-lasting suppression of HBV replication, either maintained on-therapy or sustained after stopping therapy, has been identified as the key determinant for achieving the goals of therapy, for reducing liver damage, and for preventing development of cirrhosis and/ or hepatocellular carcinoma.